2-63037581-G-A

Variant names:

• chr2-63037581-G-A
• rs1476850329
• NM_001142616.3:c.3150G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BS2_Supporting

The NM_001142616.3(EHBP1):​c.3150G>A​(p.Met1050Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000344 in 1,453,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: EHBP1 NM_001142616.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.21

Genes affected

EHBP1 (HGNC:29144): (EH domain binding protein 1) This gene encodes an Eps15 homology domain binding protein. The encoded protein may play a role in endocytic trafficking. A single nucleotide polymorphism in this gene is associated with an aggressive form of prostate cancer. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2010]

EHBP1-AS1 (HGNC:55766): (EHBP1 antisense RNA 1)

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=0.3311146).
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EHBP1	NM_001142616.3	c.3150G>A	p.Met1050Ile	missense_variant	Exon 20 of 23	ENST00000431489.6	NP_001136088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EHBP1	ENST00000431489.6	c.3150G>A	p.Met1050Ile	missense_variant	Exon 20 of 23	1	NM_001142616.3	ENSP00000403783.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1453980 Hom.: 0 Cov.: 28 AF XY: 0.00000553 AC XY: 4 AN XY: 723196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3363G>A (p.M1121I) alteration is located in exon 22 (coding exon 21) of the EHBP1 gene. This alteration results from a G to A substitution at nucleotide position 3363, causing the methionine (M) at amino acid position 1121 to be replaced by an isoleucine (I). 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	0.59
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	.;.;T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	-0.20	.;.;N;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.11	T;T;T;T
Sift4G	Uncertain	0.047	D;D;T;T
Polyphen		0.46	P;P;D;P
Vest4		0.57
MutPred		0.35		.;.;Loss of disorder (P = 0.0377);.;
MVP		0.27
MPC		1.2
ClinPred		0.90	D
GERP RS		5.3
Varity_R		0.56
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

LitVar

Other links and lift over

dbSNP: rs1476850329; hg19: chr2-63264716;