11-35139343-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000610.4(CD44):c.40C>T(p.Leu14Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,409,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

CD44
NM_000610.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.940

Publications

0 publications found

Variant links:

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]

CD44 links:

CD44-DT (HGNC:56175): (CD44 divergent transcript)

CD44-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.27287883).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD44	NM_000610.4 link	c.40C>T	p.Leu14Phe	missense_variant	Exon 1 of 18	ENST00000428726.8	NP_000601.3	P16070-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD44	ENST00000428726.8 link	c.40C>T	p.Leu14Phe	missense_variant	Exon 1 of 18	1	NM_000610.4	ENSP00000398632.2		P16070-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

167946

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.09e-7

AC:

AN:

1409450

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

696052

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32388

American (AMR)

AF:

0.00

AC:

AN:

36458

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25244

East Asian (EAS)

AF:

0.0000270

AC:

AN:

37006

South Asian (SAS)

AF:

0.00

AC:

AN:

79982

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49754

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1084578

Other (OTH)

AF:

0.00

AC:

AN:

58362

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.40C>T (p.L14F) alteration is located in exon 1 (coding exon 1) of the CD44 gene. This alteration results from a C to T substitution at nucleotide position 40, causing the leucine (L) at amino acid position 14 to be replaced by a phenylalanine (F). 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

Benign

0.098

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.67

.;D;T;.;T;.;.;.;.;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.077

LIST_S2

Uncertain

0.89

D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.047

MetaRNN

Benign

0.27

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.8

L;L;.;L;.;L;.;L;L;L

PhyloP100

0.94

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.4

D;D;D;D;.;D;.;D;D;D

REVEL

Benign

0.032

Sift

Uncertain

0.0060

D;D;D;D;.;D;.;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D;D;D;.;D;D;D

Polyphen

0.079

B;D;.;D;.;P;.;.;B;.

Vest4

0.16

MutPred

0.49

Loss of glycosylation at S18 (P = 0.1995);Loss of glycosylation at S18 (P = 0.1995);Loss of glycosylation at S18 (P = 0.1995);Loss of glycosylation at S18 (P = 0.1995);Loss of glycosylation at S18 (P = 0.1995);Loss of glycosylation at S18 (P = 0.1995);Loss of glycosylation at S18 (P = 0.1995);Loss of glycosylation at S18 (P = 0.1995);Loss of glycosylation at S18 (P = 0.1995);Loss of glycosylation at S18 (P = 0.1995);

MVP

0.53

MPC

0.82

ClinPred

0.91

GERP RS

-0.012

PromoterAI

0.041

Neutral

(source)

Varity_R

0.15

gMVP

0.77

Mutation Taster

=64/36

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over