11-35176644-G-C

Variant names:

• chr11-35176644-G-C
• rs369473842
• NM_000610.4:c.137G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000610.4(CD44):​c.137G>C​(p.Arg46Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000674 in 1,614,168 control chromosomes in the GnomAD database, including 13 homozygotes. 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. R46Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00070 (13 hom.)
• Consequence: CD44 NM_000610.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.761
• Publications: 13 publications found

Genes affected

CD44 (HGNC:1681): (CD44 molecule (IN blood group)) The protein encoded by this gene is a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion and migration. It is a receptor for hyaluronic acid (HA) and can also interact with other ligands, such as osteopontin, collagens, and matrix metalloproteinases (MMPs). This protein participates in a wide variety of cellular functions including lymphocyte activation, recirculation and homing, hematopoiesis, and tumor metastasis. Transcripts for this gene undergo complex alternative splicing that results in many functionally distinct isoforms, however, the full length nature of some of these variants has not been determined. Alternative splicing is the basis for the structural and functional diversity of this protein, and may be related to tumor metastasis. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0091403425).
• BS2: High Homozygotes in GnomAdExome4 at 13 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD44	NM_000610.4	c.137G>C	p.Arg46Pro	missense_variant	Exon 2 of 18	ENST00000428726.8	NP_000601.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD44	ENST00000428726.8	c.137G>C	p.Arg46Pro	missense_variant	Exon 2 of 18	1	NM_000610.4	ENSP00000398632.2

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00124 AC: 311 AN: 251286 AF XY: 0.00174

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000700 AC: 1024 AN: 1461838 Hom.: 13 Cov.: 31 AF XY: 0.000974 AC XY: 708 AN XY: 727218

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0109 AC: 943 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000468 AC: 52 AN: 1111976

Other (OTH) AF: 0.000431 AC: 26 AN: 60394

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000550 AC XY: 41 AN XY: 74504

African (AFR) AF: 0.0000481 AC: 2 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000893 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.00136 AC: 165

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;T;T;.;T;.;.;.;.;.;T
Eigen	Benign	-0.046
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0091	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M;.;M;.;M;.;M;M;M;.
PhyloP100		0.76
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-6.0	D;D;D;D;.;D;.;D;D;D;D
REVEL	Benign	0.18
Sift	Benign	0.033	D;D;D;D;.;D;.;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;.;D;D;D;D
Polyphen		0.96	D;P;.;P;.;P;.;.;P;.;.
Vest4		0.63
MutPred		0.76		Loss of methylation at R46 (P = 0.0145);Loss of methylation at R46 (P = 0.0145);Loss of methylation at R46 (P = 0.0145);Loss of methylation at R46 (P = 0.0145);Loss of methylation at R46 (P = 0.0145);Loss of methylation at R46 (P = 0.0145);Loss of methylation at R46 (P = 0.0145);Loss of methylation at R46 (P = 0.0145);Loss of methylation at R46 (P = 0.0145);Loss of methylation at R46 (P = 0.0145);.;
MVP		0.38
MPC		2.1
ClinPred		0.16	T
GERP RS		1.7
PromoterAI		0.016	Neutral
Varity_R		0.89
gMVP		0.97
Mutation Taster		=98/2	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: rs369473842; hg19: chr11-35198191;