rs754836509

chrX-108680694-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1 BP4_Strong BS1 BS2

The NM_033380.3(COL4A5):c.3958C>T(p.Pro1320Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,207,663 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 40 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1320L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.00013 (0 hom. 37 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.57

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 Benign. Variant got -10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_033380.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.03224808).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000127 (139/1096632) while in subpopulation EAS AF= 0.00408 (123/30177). AF 95% confidence interval is 0.00349. There are 0 homozygotes in gnomad4_exome. There are 37 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.3958C>T	p.Pro1320Ser	missense_variant	45/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.3958C>T	p.Pro1320Ser	missense_variant	45/53	1	NM_033380.3
COL4A5	ENST00000361603.7	c.3940C>T	p.Pro1314Ser	missense_variant	43/51	2		P1
COL4A5	ENST00000489230.1	n.361C>T		non_coding_transcript_exon_variant	4/8	5
COL4A5	ENST00000510690.2	n.452C>T		non_coding_transcript_exon_variant	3/11	4

Frequencies

GnomAD3 genomes AF: 0.000153 AC: 17 AN: 110981 Hom.: 0 Cov.: 22 AF XY: 0.0000903 AC XY: 3 AN XY: 33205

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.000383

Gnomad FIN AF: 0.000169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000323 AC: 59 AN: 182928 Hom.: 0 AF XY: 0.000178 AC XY: 12 AN XY: 67582

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00420

Gnomad SAS exome AF: 0.0000525

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000127 AC: 139 AN: 1096632 Hom.: 0 Cov.: 30 AF XY: 0.000102 AC XY: 37 AN XY: 362204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00408

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000119

Gnomad4 OTH exome AF: 0.0000869

GnomAD4 genome AF: 0.000153 AC: 17 AN: 111031 Hom.: 0 Cov.: 22 AF XY: 0.0000902 AC XY: 3 AN XY: 33265

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00425

Gnomad4 SAS AF: 0.000384

Gnomad4 FIN AF: 0.000169

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000234

ExAC AF: 0.000288 AC: 35

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 06, 2017

- -

X-linked Alport syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Precision Medicine Center, Zhengzhou University

-

PM1:Located in a mutational hot spot PP3:Multiple lines of computational evidence support a deleterious effect on the gene or gene product -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Uncertain	24
Dann	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.032	T;T
MetaSVM	Uncertain	0.61	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.81
Sift	Benign	0.088	T;D
Sift4G	Benign	0.12	T;T
Polyphen		0.61	.;P
Vest4		0.18
MutPred		0.78		.;Gain of relative solvent accessibility (P = 0.0082);
MVP		1.0
MPC		0.85
ClinPred		0.16	T
GERP RS		4.4
Varity_R		0.31
gMVP		0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs754836509; hg19: chrX-107923924; COSMIC: COSV60373871; COSMIC: COSV60373871;