rs759512115

chrX-108539771-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033380.3(COL4A5):c.107C>T(p.Ser36Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,096,255 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S36S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26520315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.107C>T	p.Ser36Leu	missense_variant	2/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.107C>T	p.Ser36Leu	missense_variant	2/53	1	NM_033380.3
COL4A5	ENST00000361603.7	c.107C>T	p.Ser36Leu	missense_variant	2/51	2		P1
COL4A5	ENST00000470339.1	n.291C>T		non_coding_transcript_exon_variant	2/6	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000547 AC: 1 AN: 182865 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67521

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1096255 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 1 AN XY: 361757

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000555

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	20
Dann	Uncertain	0.99
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.26	T;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.23
Sift	Benign	0.099	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0060	.;B
Vest4		0.13
MutPred		0.43		Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);
MVP		0.56
MPC		0.27
ClinPred		0.30	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs759512115; hg19: chrX-107783001;