11-64854730-A-G

Position:

• chr11-64854730-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006795.4(EHD1):​c.1208T>C​(p.Leu403Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)
• Consequence: EHD1 NM_006795.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.209

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0995374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EHD1	NM_006795.4	c.1208T>C	p.Leu403Pro	missense_variant	5/5	ENST00000320631.8	NP_006786.2
EHD1	NM_001282445.2	c.1250T>C	p.Leu417Pro	missense_variant	6/6		NP_001269374.1
EHD1	NM_001282444.2	c.1208T>C	p.Leu403Pro	missense_variant	7/7		NP_001269373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EHD1	ENST00000320631.8	c.1208T>C	p.Leu403Pro	missense_variant	5/5	1	NM_006795.4	ENSP00000320516	P1

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

Jun 21, 2023

The c.1208T>C (p.L403P) alteration is located in exon 5 (coding exon 5) of the EHD1 gene. This alteration results from a T to C substitution at nucleotide position 1208, causing the leucine (L) at amino acid position 403 to be replaced by a proline (P). 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	Uncertain	0.48
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.81
DEOGEN2	Benign	0.13	T;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.81	.;T;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.15	N;.;N;N
REVEL	Benign	0.15
Sift	Benign	0.27	T;.;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.018	B;.;B;.
Vest4		0.19
MutPred		0.48		Gain of sheet (P = 0.0101);.;Gain of sheet (P = 0.0101);.;
MVP		0.68
MPC		1.3
ClinPred		0.035	T
GERP RS		-1.3
Varity_R		0.040
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64622202;