chrX-108626357-T-C

Variant names:

• chrX-108626357-T-C
• rs2067154508
• ENST00000483338.1:c.2078T>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Moderate BP6_Moderate

The ENST00000483338.1(COL4A5):​c.2078T>C​(p.Phe693Ser) 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. 9/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. F693F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A5 ENST00000483338.1 missense
• Scores: Splicing: ADA: 0.0001088
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.503

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 538 curated pathogenic missense variants (we use a threshold of 10). The gene has 138 curated benign missense variants. Gene score misZ: 2.4995 (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.093798995).
• BP6: Variant X-108626357-T-C is Benign according to our data. Variant chrX-108626357-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2753528.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.3246+8T>C		splice_region_variant, intron_variant	Intron 36 of 52	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000483338.1	c.2078T>C	p.Phe693Ser	missense_variant	Exon 20 of 20	1		ENSP00000495685.1
COL4A5	ENST00000328300.11	c.3246+8T>C		splice_region_variant, intron_variant	Intron 36 of 52	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000361603.7	c.3246+8T>C		splice_region_variant, intron_variant	Intron 36 of 50	2		ENSP00000354505.2
COL4A5	ENST00000505728.1	c.477+8T>C		splice_region_variant, intron_variant	Intron 4 of 4	3		ENSP00000424137.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.5
DANN	Benign	0.68
DEOGEN2	Benign	0.0075	T
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.094	T
Polyphen		0.46	P
GERP RS		0.16
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0040
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

Publications

LitVar

Other links and lift over

dbSNP: rs2067154508; hg19: chrX-107869587;