rs35363062

Variant names:

• chrX-108163026-A-G
• rs35363062
• NM_033641.4:c.4082T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033641.4(COL4A6):​c.4082T>C​(p.Leu1361Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,193,027 control chromosomes in the GnomAD database, including 197 homozygotes. There are 1,639 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (99 hom., 796 hem., cov: 23)
  • Exomes 𝑓: 0.0030 (98 hom. 843 hem.)
• Consequence: COL4A6 NM_033641.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.429
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026853085).
• BP6: Variant X-108163026-A-G is Benign according to our data. Variant chrX-108163026-A-G is described in ClinVar as Benign. ClinVar VariationId is 258278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0953 is higher than 0.05.

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.4082T>C	p.Leu1361Pro	missense	Exon 41 of 45	NP_378667.1	Q14031-2
	COL4A6	NM_001287758.2		c.4133T>C	p.Leu1378Pro	missense	Exon 42 of 46	NP_001274687.1	A8MXH5
	COL4A6	NM_001847.4		c.4085T>C	p.Leu1362Pro	missense	Exon 41 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.4082T>C	p.Leu1361Pro	missense	Exon 41 of 45	ENSP00000334733.7	Q14031-2
	COL4A6	ENST00000372216.8	TSL:1	c.4085T>C	p.Leu1362Pro	missense	Exon 41 of 45	ENSP00000361290.4	Q14031-1
	COL4A6	ENST00000621266.4	TSL:1	c.4010T>C	p.Leu1337Pro	missense	Exon 40 of 44	ENSP00000482970.1	A0A087WZY5

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 3126 AN: 111284 Hom.: 99 Cov.: 23

Gnomad AFR AF: 0.0980

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00873

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00115

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000321

Gnomad OTH AF: 0.0194

GnomAD2 exomes AF: 0.00844 AC: 1369 AN: 162253 AF XY: 0.00459

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.00521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000147

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00304 AC: 3289 AN: 1081691 Hom.: 98 Cov.: 30 AF XY: 0.00240 AC XY: 843 AN XY: 351539

African (AFR) AF: 0.105 AC: 2650 AN: 25317

American (AMR) AF: 0.00625 AC: 199 AN: 31856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18828

East Asian (EAS) AF: 0.00 AC: 0 AN: 28835

South Asian (SAS) AF: 0.000255 AC: 13 AN: 50884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40370

Middle Eastern (MID) AF: 0.00344 AC: 14 AN: 4064

European-Non Finnish (NFE) AF: 0.000123 AC: 103 AN: 836071

Other (OTH) AF: 0.00682 AC: 310 AN: 45466

GnomAD4 genome AF: 0.0282 AC: 3138 AN: 111336 Hom.: 99 Cov.: 23 AF XY: 0.0237 AC XY: 796 AN XY: 33566

African (AFR) AF: 0.0982 AC: 2998 AN: 30529

American (AMR) AF: 0.00872 AC: 92 AN: 10551

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3541

South Asian (SAS) AF: 0.000766 AC: 2 AN: 2610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6079

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000321 AC: 17 AN: 52972

Other (OTH) AF: 0.0192 AC: 29 AN: 1513

Alfa AF: 0.0108 Hom.: 518

Bravo AF: 0.0335

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.105 AC: 403

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00954 AC: 1158

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Hearing loss, X-linked 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	6.0
DANN	Benign	0.32
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-1.4	N
PhyloP100		-0.43
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.68	N
REVEL	Benign	0.16
Sift	Benign	0.49	T
Sift4G	Benign	0.43	T
Polyphen		0.0040	B
Vest4		0.082
MVP		0.12
MPC		0.29
ClinPred		0.00056	T
GERP RS		1.4
Varity_R		0.059
gMVP		0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs35363062; hg19: chrX-107406256;