Genetic Variant COL4A5:c.2147-3C>T (chrX-108602961-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

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

The NM_033380.3(COL4A5):c.2147-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,050,029 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.000022 ( 0 hom. 6 hem. )

Consequence

COL4A5
NM_033380.3 splice_region, intron

Scores

Splicing: ADA: 0.002200

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.02

Publications

1 publications found

Variant links:

Genes affected

COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

COL4A5 Gene-Disease associations (from GenCC):

Alport syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, G2P
X-linked Alport syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)

COL4A5 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant X-108602961-C-T is Benign according to our data. Variant chrX-108602961-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3357915.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.2147-3C>T		splice_region_variant, intron_variant	Intron 27 of 52	ENST00000328300.11	NP_203699.1	P29400-2Q49AM6A7MBN3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL4A5	ENST00000328300.11 link	c.2147-3C>T	splice_region_variant, intron_variant	Intron 27 of 52	1	NM_033380.3	ENSP00000331902.7	P29400-2
COL4A5	ENST00000483338.1 link	c.971-3C>T	splice_region_variant, intron_variant	Intron 11 of 19	1		ENSP00000495685.1	Q49AM6
COL4A5	ENST00000361603.7 link	c.2147-3C>T	splice_region_variant, intron_variant	Intron 27 of 50	2		ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1050029

Hom.:

Cov.:

AF XY:

0.0000181

AC XY:

AN XY:

331139

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25416

American (AMR)

AF:

0.00

AC:

AN:

32191

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18720

East Asian (EAS)

AF:

0.00

AC:

AN:

29032

South Asian (SAS)

AF:

0.00

AC:

AN:

50648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38696

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3601

European-Non Finnish (NFE)

AF:

0.0000285

AC:

AN:

807479

Other (OTH)

AF:

0.00

AC:

AN:

44246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

COL4A5-related disorder

Benign:1

Apr 27, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0022

dbscSNV1_RF

Benign

0.028

SpliceAI score (max)

0.090

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over