11-35176617-A-C

Position:

• chr11-35176617-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000610.4(CD44):​c.110A>C​(p.Glu37Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CD44 NM_000610.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.38

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD44	NM_000610.4	c.110A>C	p.Glu37Ala	missense_variant	2/18	ENST00000428726.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD44	ENST00000428726.8	c.110A>C	p.Glu37Ala	missense_variant	2/18	1	NM_000610.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2023

The c.110A>C (p.E37A) alteration is located in exon 2 (coding exon 2) of the CD44 gene. This alteration results from a A to C substitution at nucleotide position 110, causing the glutamic acid (E) at amino acid position 37 to be replaced by an alanine (A). 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	0.97
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	.;T;T;.;T;.;.;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M;M;.;M;.;M;.;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.5	D;D;D;D;.;D;.;D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	D;D;D;D;.;D;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;.;D;D;D
Polyphen		1.0	D;D;.;D;.;D;.;.;D;.
Vest4		0.69
MutPred		0.61		Loss of ubiquitination at K38 (P = 0.0504);Loss of ubiquitination at K38 (P = 0.0504);Loss of ubiquitination at K38 (P = 0.0504);Loss of ubiquitination at K38 (P = 0.0504);Loss of ubiquitination at K38 (P = 0.0504);Loss of ubiquitination at K38 (P = 0.0504);Loss of ubiquitination at K38 (P = 0.0504);Loss of ubiquitination at K38 (P = 0.0504);Loss of ubiquitination at K38 (P = 0.0504);Loss of ubiquitination at K38 (P = 0.0504);
MVP		0.53
MPC		1.9
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-35198164;