NM_033380.3:c.2107A>T

Variant names:

• chrX-108601950-A-T
• rs104886155
• NM_033380.3:c.2107A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_033380.3(COL4A5):​c.2107A>T​(p.Ile703Phe) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I703V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.582
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_033380.3
• 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). 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=0.24681091).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2107A>T	p.Ile703Phe	missense_variant	Exon 27 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2107A>T	p.Ile703Phe	missense_variant	Exon 27 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.931A>T	p.Ile311Phe	missense_variant	Exon 11 of 20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.2107A>T	p.Ile703Phe	missense_variant	Exon 27 of 51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	13
DANN	Benign	0.83
DEOGEN2	Benign	0.40	.;T;T
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.87	D;T;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	0.61	N;N;.
PhyloP100		0.58
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.57	N;N;.
REVEL	Uncertain	0.43
Sift	Benign	0.73	T;T;.
Sift4G	Benign	0.71	T;T;.
Polyphen		0.35	.;B;B
Vest4		0.36
MutPred		0.56		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;
MVP		0.79
MPC		0.47
ClinPred		0.34	T
GERP RS		4.3
Varity_R		0.25
gMVP		0.53
Mutation Taster		=90/10	polymorphism

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: rs104886155; hg19: chrX-107845180;