rs2929366

Positions:

• chr3-19918264-G-A
• chr3-19918264-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_144715.4(EFHB):​c.1145C>T​(p.Thr382Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.656 in 1,609,600 control chromosomes in the GnomAD database, including 352,526 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.68 (35988 hom., cov: 29)
  • Exomes 𝑓: 0.65 (316538 hom.)
• Consequence: EFHB NM_144715.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.167

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0044816E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFHB	NM_144715.4	c.1145C>T	p.Thr382Ile	missense_variant	4/13	ENST00000295824.14	NP_653316.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHB	ENST00000295824.14	c.1145C>T	p.Thr382Ile	missense_variant	4/13	1	NM_144715.4	ENSP00000295824.9

Frequencies

GnomAD3 genomes AF: 0.681 AC: 103199 AN: 151470 Hom.: 35951 Cov.: 29

Gnomad AFR AF: 0.804

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.638

Gnomad FIN AF: 0.682

Gnomad MID AF: 0.625

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.649

GnomAD3 exomes AF: 0.614 AC: 152453 AN: 248340 Hom.: 49245 AF XY: 0.622 AC XY: 83475 AN XY: 134206

Gnomad AFR exome AF: 0.809

Gnomad AMR exome AF: 0.405

Gnomad ASJ exome AF: 0.659

Gnomad EAS exome AF: 0.327

Gnomad SAS exome AF: 0.647

Gnomad FIN exome AF: 0.688

Gnomad NFE exome AF: 0.668

Gnomad OTH exome AF: 0.621

GnomAD4 exome AF: 0.653 AC: 952661 AN: 1458014 Hom.: 316538 Cov.: 48 AF XY: 0.653 AC XY: 473658 AN XY: 725170

Gnomad4 AFR exome AF: 0.808

Gnomad4 AMR exome AF: 0.423

Gnomad4 ASJ exome AF: 0.657

Gnomad4 EAS exome AF: 0.299

Gnomad4 SAS exome AF: 0.649

Gnomad4 FIN exome AF: 0.686

Gnomad4 NFE exome AF: 0.670

Gnomad4 OTH exome AF: 0.651

GnomAD4 genome AF: 0.681 AC: 103295 AN: 151586 Hom.: 35988 Cov.: 29 AF XY: 0.678 AC XY: 50244 AN XY: 74076

Gnomad4 AFR AF: 0.805

Gnomad4 AMR AF: 0.550

Gnomad4 ASJ AF: 0.653

Gnomad4 EAS AF: 0.329

Gnomad4 SAS AF: 0.638

Gnomad4 FIN AF: 0.682

Gnomad4 NFE AF: 0.667

Gnomad4 OTH AF: 0.644

Alfa AF: 0.667 Hom.: 32355

Bravo AF: 0.669

ESP6500AA AF: 0.805 AC: 3546

ESP6500EA AF: 0.666 AC: 5725

ExAC AF: 0.629 AC: 76422

Asia WGS AF: 0.491 AC: 1711 AN: 3478

EpiCase AF: 0.648

EpiControl AF: 0.654

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.7
DANN	Benign	0.82
DEOGEN2	Benign	0.00010	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0058	N
LIST_S2	Benign	0.043	T;T;T
MetaRNN	Benign	0.0000010	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.73	N;N;N
REVEL	Benign	0.025
Sift	Benign	0.56	T;T;T
Sift4G	Benign	0.53	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.062
MPC		0.034
ClinPred		0.0095	T
GERP RS		1.6
Varity_R		0.019
gMVP		0.14

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: rs2929366; hg19: chr3-19959756; COSMIC: COSV55546252;