NM_001335.4:c.415A>G

Variant names:

• chr11-65882303-A-G
• rs604630
• NM_001335.4:c.415A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001335.4(CTSW):​c.415A>G​(p.Ser139Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.987 in 1,614,124 control chromosomes in the GnomAD database, including 788,721 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.94 (67445 hom., cov: 32)
  • Exomes 𝑓: 0.99 (721276 hom.)
• Consequence: CTSW NM_001335.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.913

Genes affected

CTSW (HGNC:2546): (cathepsin W) The protein encoded by this gene, a member of the peptidase C1 family, is a cysteine proteinase that may have a specific function in the mechanism or regulation of T-cell cytolytic activity. The encoded protein is found associated with the membrane inside the endoplasmic reticulum of natural killer and cytotoxic T-cells. Expression of this gene is up-regulated by interleukin-2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6164156E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSW	NM_001335.4	c.415A>G	p.Ser139Gly	missense_variant	Exon 4 of 10	ENST00000307886.8	NP_001326.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSW	ENST00000307886.8	c.415A>G	p.Ser139Gly	missense_variant	Exon 4 of 10	1	NM_001335.4	ENSP00000311300.3

Frequencies

GnomAD3 genomes AF: 0.936 AC: 142446 AN: 152142 Hom.: 67405 Cov.: 32

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.993

Gnomad AMR AF: 0.969

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.965

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.948

GnomAD3 exomes AF: 0.983 AC: 247185 AN: 251410 Hom.: 121888 AF XY: 0.988 AC XY: 134224 AN XY: 135884

Gnomad AFR exome AF: 0.781

Gnomad AMR exome AF: 0.988

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 0.999

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.991

GnomAD4 exome AF: 0.993 AC: 1451250 AN: 1461864 Hom.: 721276 Cov.: 67 AF XY: 0.994 AC XY: 722679 AN XY: 727232

Gnomad4 AFR exome AF: 0.772

Gnomad4 AMR exome AF: 0.986

Gnomad4 ASJ exome AF: 0.999

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.999

Gnomad4 OTH exome AF: 0.983

GnomAD4 genome AF: 0.936 AC: 142544 AN: 152260 Hom.: 67445 Cov.: 32 AF XY: 0.940 AC XY: 69955 AN XY: 74452

Gnomad4 AFR AF: 0.783

Gnomad4 AMR AF: 0.969

Gnomad4 ASJ AF: 0.999

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.949

Alfa AF: 0.989 Hom.: 132919

Bravo AF: 0.929

TwinsUK AF: 0.999 AC: 3704

ALSPAC AF: 0.999 AC: 3849

ESP6500AA AF: 0.805 AC: 3544

ESP6500EA AF: 0.999 AC: 8585

ExAC AF: 0.980 AC: 118960

Asia WGS AF: 0.988 AC: 3434 AN: 3478

EpiCase AF: 0.998

EpiControl AF: 0.998

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.021
DANN	Benign	0.34
DEOGEN2	Benign	0.30	T;T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.13	T;T;T
MetaRNN	Benign	0.0000016	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.7	N;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	3.1	N;N;N
REVEL	Benign	0.010
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.027
MPC		0.056
ClinPred		0.0018	T
GERP RS		-1.7
Varity_R		0.030
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs604630; hg19: chr11-65649774;