rs1194273935

Variant names:

• chrX-108157031-C-G
• rs1194273935
• NM_033641.4:c.5042G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-108157031-C-G
• chrX-108157031-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033641.4(COL4A6):​c.5042G>C​(p.Ser1681Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,098,082 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1681N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: COL4A6 NM_033641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.07
• Publications: 0 publications found

Genes affected

COL4A6 (HGNC:2208): (collagen type IV alpha 6 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. 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, alpha 5 type IV collagen, so that the gene pair shares a common promoter. Deletions in the alpha 5 gene that extend into the alpha 6 gene result in diffuse leiomyomatosis accompanying the X-linked Alport syndrome caused by the deletion in the alpha 5 gene. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2013]

COL4A6 Gene-Disease associations (from GenCC):

• hearing loss, X-linked 6

  Inheritance: XL Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• X-linked nonsyndromic hearing loss

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• premature ovarian failure 1

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033641.4. 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
	COL4A6	NM_033641.4	MANE Select	c.5042G>C	p.Ser1681Thr	missense	Exon 45 of 45	NP_378667.1	Q14031-2
	COL4A6	NM_001287758.2		c.5093G>C	p.Ser1698Thr	missense	Exon 46 of 46	NP_001274687.1	A8MXH5
	COL4A6	NM_001847.4		c.5045G>C	p.Ser1682Thr	missense	Exon 45 of 45	NP_001838.2	Q14031-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A6	ENST00000334504.12	TSL:5 MANE Select	c.5042G>C	p.Ser1681Thr	missense	Exon 45 of 45	ENSP00000334733.7	Q14031-2
	COL4A6	ENST00000372216.8	TSL:1	c.5045G>C	p.Ser1682Thr	missense	Exon 45 of 45	ENSP00000361290.4	Q14031-1
	COL4A6	ENST00000621266.4	TSL:1	c.4970G>C	p.Ser1657Thr	missense	Exon 44 of 44	ENSP00000482970.1	A0A087WZY5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182909 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098082 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363448

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4124

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842063

Other (OTH) AF: 0.00 AC: 0 AN: 46080

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		6.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.96	D
Vest4		0.43
MutPred		0.81		Gain of sheet (P = 0.0827)
MVP		0.98
MPC		0.18
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.82
gMVP		0.93
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1194273935; hg19: chrX-107400261;