9-134802991-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000093.5(COL5A1):c.3110C>T(p.Thr1037Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000901 in 1,598,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1037T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

COL5A1
NM_000093.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 4.91

Publications

0 publications found

Variant links:

Genes affected

COL5A1 (HGNC:2209): (collagen type V alpha 1 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. The encoded procollagen protein occurs commonly as the heterotrimer pro-alpha1(V)-pro-alpha1(V)-pro-alpha2(V). Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

COL5A1 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Ehlers-Danlos syndrome, classic type
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, PanelApp Australia, Genomics England PanelApp
Ehlers-Danlos syndrome, classic type, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
arterial disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

COL5A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25527102).

BP6

Variant 9-134802991-C-T is Benign according to our data. Variant chr9-134802991-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212955.

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL5A1	NM_000093.5 link	c.3110C>T	p.Thr1037Met	missense_variant	Exon 39 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1 link	c.3110C>T	p.Thr1037Met	missense_variant	Exon 39 of 66		NP_001265003.1
COL5A1	XM_017014266.3 link	c.3110C>T	p.Thr1037Met	missense_variant	Exon 39 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 link	c.3110C>T	p.Thr1037Met	missense_variant	Exon 39 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4 link	c.3110C>T	p.Thr1037Met	missense_variant	Exon 39 of 66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000783

AC:

AN:

217014

AF XY:

0.0000683

show subpopulations

Gnomad AFR exome

AF:

0.000149

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000731

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000913

AC:

132

AN:

1446344

Hom.:

Cov.:

AF XY:

0.0000905

AC XY:

AN XY:

717978

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33352

American (AMR)

AF:

0.000214

AC:

AN:

42118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25650

East Asian (EAS)

AF:

0.0000764

AC:

AN:

39266

South Asian (SAS)

AF:

0.00

AC:

AN:

83586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51870

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0000996

AC:

110

AN:

1104948

Other (OTH)

AF:

0.000100

AC:

AN:

59812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41578

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000197

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000912

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T1037M variant (also known as c.3110C>T), located in coding exon 39 of the COL5A1 gene, results from a C to T substitution at nucleotide position 3110. The threonine at codon 1037 is replaced by methionine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided

Uncertain:1

Jun 09, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (HGMD, PMID: 22696272); This variant is associated with the following publications: (PMID: 22696272) -

Ehlers-Danlos syndrome, classic type, 1;C5543412:Fibromuscular dysplasia, multifocal

Uncertain:1

Sep 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jun 19, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: COL5A1 c.3110C>T (p.Thr1037Met) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 9e-05 in 1598662 control chromosomes, predominantly at a frequency of 0.00017 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL5A1 causing Ehlers-Danlos syndrome, classic type, Ehlers-Danlos syndrome, classic type, 1 phenotype (3.1e-05). c.3110C>T has not been observed in individual(s) affected with COL5A1-related conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31141158, 26566670). ClinVar contains an entry for this variant (Variation ID: 212955). Based on the evidence outlined above, the variant was classified as likely benign. -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.32

T;T

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.26

T;T

MetaSVM

Uncertain

0.55

MutationAssessor

Benign

0.53

N;N

PhyloP100

4.9

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.5

N;.

REVEL

Uncertain

0.46

Sift

Uncertain

0.023

D;.

Sift4G

Uncertain

0.052

T;T

Polyphen

0.99

D;.

Vest4

0.39

MVP

0.71

MPC

0.56

ClinPred

0.15

GERP RS

4.3

Varity_R

0.069

gMVP

0.091

Mutation Taster

=57/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over