X-108601436-G-T

Variant names:

• chrX-108601436-G-T
• rs34077552
• NM_033380.3:c.1992G>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033380.3(COL4A5):​c.1992G>T​(p.Lys664Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,204,997 control chromosomes in the GnomAD database, including 59 homozygotes. There are 4,497 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 (★★). Synonymous variant affecting the same amino acid position (i.e. K664K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0076 (6 hom., 210 hem., cov: 21)
  • Exomes 𝑓: 0.012 (53 hom. 4287 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.00600
• Publications: 8 publications found

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]

COL4A5 Gene-Disease associations (from GenCC):

• Alport syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, G2P
• X-linked Alport syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in NM_033380.3
• 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). Trascript score misZ: NaN (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=0.0068911016).
• BP6: Variant X-108601436-G-T is Benign according to our data. Variant chrX-108601436-G-T is described in ClinVar as Benign. ClinVar VariationId is 24469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00764 (844/110452) while in subpopulation SAS AF = 0.0125 (32/2551). AF 95% confidence interval is 0.0103. There are 6 homozygotes in GnomAd4. There are 210 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033380.3. 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
	COL4A5	NM_033380.3	MANE Select	c.1992G>T	p.Lys664Asn	missense	Exon 26 of 53	NP_203699.1
	COL4A5	NM_000495.5		c.1992G>T	p.Lys664Asn	missense	Exon 26 of 51	NP_000486.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	ENST00000328300.11	TSL:1 MANE Select	c.1992G>T	p.Lys664Asn	missense	Exon 26 of 53	ENSP00000331902.7
	COL4A5	ENST00000483338.1	TSL:1	c.816G>T	p.Lys272Asn	missense	Exon 10 of 20	ENSP00000495685.1
	COL4A5	ENST00000361603.7	TSL:2	c.1992G>T	p.Lys664Asn	missense	Exon 26 of 51	ENSP00000354505.2

Frequencies

GnomAD3 genomes AF: 0.00764 AC: 844 AN: 110426 Hom.: 6 Cov.: 21

Gnomad AFR AF: 0.00211

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.00375

Gnomad ASJ AF: 0.00758

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0125

Gnomad FIN AF: 0.00555

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00952

GnomAD2 exomes AF: 0.00797 AC: 1441 AN: 180748 AF XY: 0.00882

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00834

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00536

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.00739

GnomAD4 exome AF: 0.0116 AC: 12683 AN: 1094545 Hom.: 53 Cov.: 29 AF XY: 0.0119 AC XY: 4287 AN XY: 360643

African (AFR) AF: 0.00141 AC: 37 AN: 26314

American (AMR) AF: 0.00316 AC: 111 AN: 35120

Ashkenazi Jewish (ASJ) AF: 0.00837 AC: 162 AN: 19351

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30127

South Asian (SAS) AF: 0.0148 AC: 797 AN: 53723

European-Finnish (FIN) AF: 0.00562 AC: 227 AN: 40416

Middle Eastern (MID) AF: 0.0122 AC: 40 AN: 3272

European-Non Finnish (NFE) AF: 0.0129 AC: 10877 AN: 840308

Other (OTH) AF: 0.00939 AC: 431 AN: 45914

GnomAD4 genome AF: 0.00764 AC: 844 AN: 110452 Hom.: 6 Cov.: 21 AF XY: 0.00641 AC XY: 210 AN XY: 32756

African (AFR) AF: 0.00211 AC: 64 AN: 30385

American (AMR) AF: 0.00375 AC: 39 AN: 10399

Ashkenazi Jewish (ASJ) AF: 0.00758 AC: 20 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3515

South Asian (SAS) AF: 0.0125 AC: 32 AN: 2551

European-Finnish (FIN) AF: 0.00555 AC: 32 AN: 5761

Middle Eastern (MID) AF: 0.0141 AC: 3 AN: 213

European-Non Finnish (NFE) AF: 0.0110 AC: 583 AN: 52825

Other (OTH) AF: 0.00940 AC: 14 AN: 1489

Alfa AF: 0.00991 Hom.: 523

Bravo AF: 0.00783

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0104 AC: 30

ESP6500AA AF: 0.00183 AC: 7

ESP6500EA AF: 0.0131 AC: 88

ExAC AF: 0.00792 AC: 962

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Lys664Asn in exon 26 of COL4A5: This variant is not expected to have clinical significance because it has been identified in 1.47% (127/8628) of South Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs34077552).

Nov 20, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Jan 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17396119, 11462238, 8940267, 17660027)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

X-linked Alport syndrome Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Atypical hemolytic-uremic syndrome Benign:1

Oct 05, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Uncertain	0.46	T
FATHMM_MKL	Benign	0.054	N
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.42	N
PhyloP100		-0.0060
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.17
Sift	Benign	0.29	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.072
MutPred		0.23		Loss of methylation at K664 (P = 0.0025)
MVP		0.48
MPC		0.35
ClinPred		0.0015	T
GERP RS		-0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.63
Mutation Taster		=99/1	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: rs34077552; hg19: chrX-107844666; COSMIC: COSV60375567;