NM_000090.4:c.515A>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBP6BS1

The NM_000090.4(COL3A1):c.515A>C(p.Tyr172Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,612,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y172C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

COL3A1
NM_000090.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.432

Publications

0 publications found

Variant links:

Genes affected

COL3A1 (HGNC:2201): (collagen type III alpha 1 chain) This gene encodes the pro-alpha1 chains of type III collagen, a fibrillar collagen that is found in extensible connective tissues such as skin, lung, uterus, intestine and the vascular system, frequently in association with type I collagen. Mutations in this gene are associated with Ehlers-Danlos syndrome type IV, and with aortic and arterial aneurysms. [provided by R. Dalgleish, Feb 2008]

COL3A1 Gene-Disease associations (from GenCC):

autosomal dominant Ehlers-Danlos syndrome, vascular type
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
Ehlers-Danlos syndrome, vascular type
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
polymicrogyria with or without vascular-type Ehlers-Danlos syndrome
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

COL3A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_000090.4

PP2

Missense variant in the COL3A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 495 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 4.0879 (above the threshold of 3.09). Trascript score misZ: 4.5995 (above the threshold of 3.09). GenCC associations: The gene is linked to Ehlers-Danlos syndrome, vascular type, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome, autosomal dominant Ehlers-Danlos syndrome, vascular type.

BP4

Computational evidence support a benign effect (MetaRNN=0.067662776).

BP6

Variant 2-188987126-A-C is Benign according to our data. Variant chr2-188987126-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 263946.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000046 (7/152046) while in subpopulation SAS AF = 0.000827 (4/4834). AF 95% confidence interval is 0.000282. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000090.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL3A1	NM_000090.4	MANE Select	c.515A>C	p.Tyr172Ser	missense	Exon 5 of 51	NP_000081.2	P02461-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL3A1	ENST00000304636.9	TSL:1 MANE Select	c.515A>C	p.Tyr172Ser	missense	Exon 5 of 51	ENSP00000304408.4	P02461-1
COL3A1	ENST00000450867.2	TSL:1	c.515A>C	p.Tyr172Ser	missense	Exon 5 of 50	ENSP00000415346.2	H7C435
COL3A1	ENST00000879201.1		c.506A>C	p.Tyr169Ser	missense	Exon 5 of 51	ENSP00000549260.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000956

AC:

AN:

250950

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1460080

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

726460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33434

American (AMR)

AF:

0.0000224

AC:

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.000360

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1110626

Other (OTH)

AF:

0.0000332

AC:

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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:

0.0000460

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.0000657

AC:

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000827

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67980

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.0000955

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ehlers-Danlos syndrome, type 4 (2)

Familial thoracic aortic aneurysm and aortic dissection (2)

not provided (2)

Ehlers-Danlos syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Uncertain

0.60

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.068

MetaSVM

Benign

-0.44

MutationAssessor

Benign

-0.14

PhyloP100

0.43

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.94

REVEL

Uncertain

0.42

Sift

Benign

0.86

Sift4G

Benign

0.43

Polyphen

0.49

Vest4

0.38

MVP

0.79

MPC

0.89

ClinPred

0.059

GERP RS

-1.0

Varity_R

0.079

gMVP

0.88

Mutation Taster

=87/13

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over