11-35176696-G-T

Variant names:

• chr11-35176696-G-T
• NM_000610.4:c.189G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000610.4(CD44):​c.189G>T​(p.Met63Ile) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CD44 NM_000610.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3129881).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD44	NM_000610.4	c.189G>T	p.Met63Ile	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.189G>T	p.Met63Ile	missense_variant	Exon 2 of 18	1	NM_000610.4	ENSP00000398632.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.189G>T (p.M63I) alteration is located in exon 2 (coding exon 2) of the CD44 gene. This alteration results from a G to T substitution at nucleotide position 189, causing the methionine (M) at amino acid position 63 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T;T;.;T;.;.;.;.;.;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.3	L;L;.;L;.;L;.;L;L;L;.
PhyloP100		2.5
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.2	D;D;D;D;.;D;.;D;D;D;D
REVEL	Benign	0.085
Sift	Benign	0.031	D;D;D;D;.;D;.;D;D;D;D
Sift4G	Uncertain	0.031	D;D;D;D;T;D;.;D;D;D;D
Polyphen		0.27	B;B;.;B;.;B;.;.;B;.;.
Vest4		0.41
MutPred		0.37		Loss of ubiquitination at K68 (P = 0.1016);Loss of ubiquitination at K68 (P = 0.1016);Loss of ubiquitination at K68 (P = 0.1016);Loss of ubiquitination at K68 (P = 0.1016);Loss of ubiquitination at K68 (P = 0.1016);Loss of ubiquitination at K68 (P = 0.1016);Loss of ubiquitination at K68 (P = 0.1016);Loss of ubiquitination at K68 (P = 0.1016);Loss of ubiquitination at K68 (P = 0.1016);Loss of ubiquitination at K68 (P = 0.1016);.;
MVP		0.40
MPC		0.94
ClinPred		0.85	D
GERP RS		5.8
PromoterAI		-0.021	Neutral
Varity_R		0.64
gMVP		0.70
Mutation Taster		=77/23	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

hg19: chr11-35198243;