3-19888510-C-A

Variant names:

• chr3-19888510-C-A
• rs746293003
• NM_144715.4:c.1867G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_144715.4(EFHB):​c.1867G>T​(p.Ala623Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,425,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A623V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EFHB NM_144715.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.20
• Publications: 3 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2881348).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144715.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFHB	NM_144715.4	MANE Select	c.1867G>T	p.Ala623Ser	missense	Exon 10 of 13	NP_653316.3
	EFHB	NM_001330688.2		c.1477G>T	p.Ala493Ser	missense	Exon 12 of 15	NP_001317617.1	Q8N7U6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFHB	ENST00000295824.14	TSL:1 MANE Select	c.1867G>T	p.Ala623Ser	missense	Exon 10 of 13	ENSP00000295824.9	Q8N7U6-1
	EFHB	ENST00000344838.8	TSL:2	c.1477G>T	p.Ala493Ser	missense	Exon 12 of 15	ENSP00000342263.4	Q8N7U6-3
	EFHB	ENST00000467602.5	TSL:3	n.203-3895G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000152 AC: 3 AN: 197868 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1425194 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 705330

African (AFR) AF: 0.00 AC: 0 AN: 32810

American (AMR) AF: 0.0000769 AC: 3 AN: 39006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25538

East Asian (EAS) AF: 0.00 AC: 0 AN: 38694

South Asian (SAS) AF: 0.00 AC: 0 AN: 81464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091670

Other (OTH) AF: 0.00 AC: 0 AN: 59022

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000166 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.95	L
PhyloP100		1.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.34
Sift	Benign	0.17	T
Sift4G	Benign	0.15	T
Polyphen		0.41	B
Vest4		0.22
MutPred		0.57		Loss of catalytic residue at A623 (P = 0.0291)
MVP		0.64
MPC		0.086
ClinPred		0.62	D
GERP RS		4.9
Varity_R		0.21
gMVP		0.35
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs746293003; hg19: chr3-19930002; COSMIC: COSV55546285;