11-35208126-T-C

Variant names:

• chr11-35208126-T-C
• rs1467558
• NM_000610.4:c.1436T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• 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
• Publications: 73 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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000610.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD44	NM_000610.4	MANE Select	c.1436T>C	p.Ile479Thr	missense	Exon 12 of 18	NP_000601.3
	CD44	NM_001440324.1		c.1439T>C	p.Ile480Thr	missense	Exon 12 of 18	NP_001427253.1
	CD44	NM_001440325.1		c.1433T>C	p.Ile478Thr	missense	Exon 12 of 18	NP_001427254.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD44	ENST00000428726.8	TSL:1 MANE Select	c.1436T>C	p.Ile479Thr	missense	Exon 12 of 18	ENSP00000398632.2
	CD44	ENST00000415148.6	TSL:1	c.1307T>C	p.Ile436Thr	missense	Exon 11 of 17	ENSP00000389830.2
	CD44	ENST00000433892.6	TSL:1	c.689T>C	p.Ile230Thr	missense	Exon 6 of 12	ENSP00000392331.2

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

GnomAD2 exomes AF: 0.881 AC: 221102 AN: 251076 AF XY: 0.878

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 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

African (AFR) AF: 0.971 AC: 32366 AN: 33336

American (AMR) AF: 0.926 AC: 41374 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.916 AC: 23892 AN: 26076

East Asian (EAS) AF: 1.00 AC: 39634 AN: 39642

South Asian (SAS) AF: 0.950 AC: 81773 AN: 86098

European-Finnish (FIN) AF: 0.842 AC: 44967 AN: 53394

Middle Eastern (MID) AF: 0.936 AC: 5391 AN: 5758

European-Non Finnish (NFE) AF: 0.804 AC: 888779 AN: 1105202

Other (OTH) AF: 0.850 AC: 51131 AN: 60178

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

African (AFR) AF: 0.967 AC: 40173 AN: 41564

American (AMR) AF: 0.888 AC: 13572 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.917 AC: 3183 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5184 AN: 5192

South Asian (SAS) AF: 0.953 AC: 4592 AN: 4820

European-Finnish (FIN) AF: 0.848 AC: 8980 AN: 10592

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.810 AC: 55100 AN: 68010

Other (OTH) AF: 0.876 AC: 1851 AN: 2112

Alfa AF: 0.839 Hom.: 194148

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

Oct 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

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
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	7.0e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.8	N
PhyloP100		2.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	2.5	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.024
MPC		0.050
ClinPred		0.0078	T
GERP RS		6.2
Varity_R		0.032
gMVP		0.052
Mutation Taster		=93/7	polymorphism (auto)

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: rs1467558; hg19: chr11-35229673; COSMIC: COSV107209872; COSMIC: COSV107209872;