11-35208126-T-C

Position:

• chr11-35208126-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000610.4(CD44):​c.1436T>C​(p.Ile479Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.836 in 1,606,644 control chromosomes in the GnomAD database, including 564,645 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.88 (59049 hom., cov: 33)
  • Exomes 𝑓: 0.83 (505596 hom.)
• Consequence: CD44 NM_000610.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.13

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.0478313E-7).
• BP6: Variant 11-35208126-T-C is Benign according to our data. Variant chr11-35208126-T-C is described in ClinVar as [Benign]. Clinvar id is 3058927.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD44	NM_000610.4	c.1436T>C	p.Ile479Thr	missense_variant	12/18	ENST00000428726.8	NP_000601.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD44	ENST00000428726.8	c.1436T>C	p.Ile479Thr	missense_variant	12/18	1	NM_000610.4	ENSP00000398632.2

Frequencies

GnomAD3 genomes AF: 0.878 AC: 133510 AN: 152142 Hom.: 58984 Cov.: 33

Gnomad AFR AF: 0.966

Gnomad AMI AF: 0.794

Gnomad AMR AF: 0.887

Gnomad ASJ AF: 0.917

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.953

Gnomad FIN AF: 0.848

Gnomad MID AF: 0.937

Gnomad NFE AF: 0.810

Gnomad OTH AF: 0.875

GnomAD3 exomes AF: 0.881 AC: 221102 AN: 251076 Hom.: 97954 AF XY: 0.878 AC XY: 119178 AN XY: 135678

Gnomad AFR exome AF: 0.968

Gnomad AMR exome AF: 0.929

Gnomad ASJ exome AF: 0.914

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.953

Gnomad FIN exome AF: 0.845

Gnomad NFE exome AF: 0.819

Gnomad OTH exome AF: 0.873

GnomAD4 exome AF: 0.831 AC: 1209307 AN: 1454384 Hom.: 505596 Cov.: 32 AF XY: 0.835 AC XY: 604401 AN XY: 723996

Gnomad4 AFR exome AF: 0.971

Gnomad4 AMR exome AF: 0.926

Gnomad4 ASJ exome AF: 0.916

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.950

Gnomad4 FIN exome AF: 0.842

Gnomad4 NFE exome AF: 0.804

Gnomad4 OTH exome AF: 0.850

GnomAD4 genome AF: 0.878 AC: 133633 AN: 152260 Hom.: 59049 Cov.: 33 AF XY: 0.883 AC XY: 65757 AN XY: 74440

Gnomad4 AFR AF: 0.967

Gnomad4 AMR AF: 0.888

Gnomad4 ASJ AF: 0.917

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.953

Gnomad4 FIN AF: 0.848

Gnomad4 NFE AF: 0.810

Gnomad4 OTH AF: 0.876

Alfa AF: 0.831 Hom.: 131801

Bravo AF: 0.884

TwinsUK AF: 0.800 AC: 2967

ALSPAC AF: 0.799 AC: 3080

ESP6500AA AF: 0.960 AC: 4228

ESP6500EA AF: 0.814 AC: 6994

ExAC AF: 0.881 AC: 106921

Asia WGS AF: 0.975 AC: 3391 AN: 3478

EpiCase AF: 0.821

EpiControl AF: 0.822

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CD44-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.68
DEOGEN2	Benign	0.22	T;.;.;.;.;T;.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.10	T;T;T;T;T;T;T;T
MetaRNN	Benign	7.0e-7	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.8	N;.;.;.;.;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	2.5	N;N;N;.;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;T;T;.;T;T;T;T
Sift4G	Benign	1.0	T;T;T;.;T;T;T;T
Polyphen		0.0	B;B;B;.;.;.;.;.
Vest4		0.024
MPC		0.050
ClinPred		0.0078	T
GERP RS		6.2
Varity_R		0.032
gMVP		0.052

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

LitVar

Other links and lift over

dbSNP: rs1467558; hg19: chr11-35229673;