Genetic Variant EHD1:p.Glu400Lys (chr11-64854740-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006795.4(EHD1):c.1198G>A(p.Glu400Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,788 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

EHD1
NM_006795.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.83

Variant links:

Genes affected

EHD1 (HGNC:3242): (EH domain containing 1) This gene belongs to a highly conserved gene family encoding EPS15 homology (EH) domain-containing proteins. The protein-binding EH domain was first noted in EPS15, a substrate for the epidermal growth factor receptor. The EH domain has been shown to be an important motif in proteins involved in protein-protein interactions and in intracellular sorting. The protein encoded by this gene is thought to play a role in the endocytosis of IGF1 receptors. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2013]

EHD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EHD1	NM_006795.4 link	c.1198G>A	p.Glu400Lys	missense_variant	Exon 5 of 5	ENST00000320631.8	NP_006786.2	Q9H4M9B2R5U3
EHD1	NM_001282445.2 link	c.1240G>A	p.Glu414Lys	missense_variant	Exon 6 of 6		NP_001269374.1	Q9H4M9A0A024R571
EHD1	NM_001282444.2 link	c.1198G>A	p.Glu400Lys	missense_variant	Exon 7 of 7		NP_001269373.1	Q9H4M9B2R5U3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EHD1	ENST00000320631.8 link	c.1198G>A	p.Glu400Lys	missense_variant	Exon 5 of 5	1	NM_006795.4	ENSP00000320516.3		Q9H4M9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249136

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000137

AC:

AN:

1459788

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726314

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1198G>A (p.E400K) alteration is located in exon 5 (coding exon 5) of the EHD1 gene. This alteration results from a G to A substitution at nucleotide position 1198, causing the glutamic acid (E) at amino acid position 400 to be replaced by a lysine (K). 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

0.17

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;T;D;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.97

.;D;D;D

M_CAP

Benign

0.040

MetaRNN

Uncertain

0.68

D;D;D;D

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.6

M;.;M;.

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.6

D;.;D;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.0030

D;.;D;D

Sift4G

Benign

0.095

T;T;T;T

Polyphen

0.70

P;.;P;.

Vest4

0.78

MutPred

0.45

Loss of loop (P = 0.0022);.;Loss of loop (P = 0.0022);.;

MVP

0.86

MPC

0.99

ClinPred

0.94

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.54

gMVP

0.89

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over