X-108170621-T-G

Variant names:

• chrX-108170621-T-G
• rs34466065
• NM_033641.4:c.3481A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033641.4(COL4A6):​c.3481A>C​(p.Ile1161Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. I1161V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A6 NM_033641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.422
• 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), ClinGen, Ambry Genetics, PanelApp Australia
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17096373).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A6	NM_033641.4	MANE Select	c.3481A>C	p.Ile1161Leu	missense	Exon 35 of 45	NP_378667.1
	COL4A6	NM_001287758.2		c.3532A>C	p.Ile1178Leu	missense	Exon 36 of 46	NP_001274687.1
	COL4A6	NM_001847.4		c.3484A>C	p.Ile1162Leu	missense	Exon 35 of 45	NP_001838.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A6	ENST00000334504.12	TSL:5 MANE Select	c.3481A>C	p.Ile1161Leu	missense	Exon 35 of 45	ENSP00000334733.7
	COL4A6	ENST00000372216.8	TSL:1	c.3484A>C	p.Ile1162Leu	missense	Exon 35 of 45	ENSP00000361290.4
	COL4A6	ENST00000621266.4	TSL:1	c.3481A>C	p.Ile1161Leu	missense	Exon 35 of 44	ENSP00000482970.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	2.3
DANN	Benign	0.85
DEOGEN2	Benign	0.28	T
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.82	L
PhyloP100		-0.42
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.089
Sift	Benign	0.39	T
Sift4G	Benign	0.14	T
Polyphen		0.24	B
Vest4		0.14
MutPred		0.24		Loss of catalytic residue at P1164 (P = 0.0374)
MVP		0.73
MPC		0.34
ClinPred		0.079	T
GERP RS		-2.0
Varity_R		0.096
gMVP		0.54
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs34466065; hg19: chrX-107413851;