3-19888592-C-G

Position:

• chr3-19888592-C-G

Variant summary

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

The ENST00000295824.14(EFHB):​c.1785G>C​(p.Leu595Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EFHB ENST00000295824.14 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48

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 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/exons	MANE	Protein	UniProt
EFHB	NM_144715.4	c.1785G>C	p.Leu595Phe	missense_variant	10/13	ENST00000295824.14	NP_653316.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFHB	ENST00000295824.14	c.1785G>C	p.Leu595Phe	missense_variant	10/13	1	NM_144715.4	ENSP00000295824	P2
EFHB	ENST00000344838.8	c.1395G>C	p.Leu465Phe	missense_variant	12/15	2		ENSP00000342263	A2
EFHB	ENST00000467602.5	n.203-3977G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Feb 22, 2023

The c.1785G>C (p.L595F) alteration is located in exon 10 (coding exon 10) of the EFHB gene. This alteration results from a G to C substitution at nucleotide position 1785, causing the leucine (L) at amino acid position 595 to be replaced by a phenylalanine (F). 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	0.34
BayesDel_addAF	Benign	0.00039	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	0.061
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.68	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.36
Sift	Benign	0.064	T;T
Sift4G	Uncertain	0.011	D;D
Polyphen		0.79	P;D
Vest4		0.39
MutPred		0.43		Loss of ubiquitination at K600 (P = 0.1423);.;
MVP		0.75
MPC		0.19
ClinPred		0.74	D
GERP RS		2.9
Varity_R		0.34
gMVP		0.30

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: chr3-19930084;