Genetic Variant EFHB:p.Val658Ile (chr3-19884577-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_144715.4(EFHB):c.1972G>A(p.Val658Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

EFHB
NM_144715.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.745

Variant links:

Genes affected

EFHB (HGNC:26330): (EF-hand domain family member B) Enables calcium ion sensor activity. Involved in negative regulation of protein binding activity; regulation of calcineurin-NFAT signaling cascade; and regulation of store-operated calcium entry. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

EFHB links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05389905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFHB	NM_144715.4 link	c.1972G>A	p.Val658Ile	missense_variant	Exon 11 of 13	ENST00000295824.14	NP_653316.3	Q8N7U6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EFHB	ENST00000295824.14 link	c.1972G>A	p.Val658Ile	missense_variant	Exon 11 of 13	1	NM_144715.4	ENSP00000295824.9	Q8N7U6-1
EFHB	ENST00000344838.8 link	c.1582G>A	p.Val528Ile	missense_variant	Exon 13 of 15	2		ENSP00000342263.4	Q8N7U6-3
EFHB	ENST00000467602.5 link	n.241G>A		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461666

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727116

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1972G>A (p.V658I) alteration is located in exon 11 (coding exon 11) of the EFHB gene. This alteration results from a G to A substitution at nucleotide position 1972, causing the valine (V) at amino acid position 658 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

Benign

0.073

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.63

DANN

Benign

0.54

DEOGEN2

Benign

0.00061

T;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.51

T;T

M_CAP

Benign

0.0045

MetaRNN

Benign

0.054

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.39

N;N

REVEL

Benign

0.015

Sift

Benign

0.22

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.011

B;B

Vest4

0.042

MutPred

0.25

Loss of helix (P = 0.0626);.;

MVP

0.43

MPC

0.030

ClinPred

0.48

GERP RS

-0.082

Varity_R

0.030

gMVP

0.19

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over