17-62391927-A-G

Variant names:

• chr17-62391927-A-G
• NM_173503.4:c.257A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173503.4(EFCAB3):​c.257A>G​(p.His86Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 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: 0.0000048 (0 hom.)
• Consequence: EFCAB3 NM_173503.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.443

Genes affected

EFCAB3 (HGNC:26379): (EF-hand calcium binding domain 3) Predicted to enable calcium ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16172662).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFCAB3	NM_173503.4	c.257A>G	p.His86Arg	missense_variant	Exon 4 of 10	ENST00000305286.8	NP_775774.1
EFCAB3	NM_001144933.2	c.413A>G	p.His138Arg	missense_variant	Exon 6 of 12		NP_001138405.1
EFCAB3	XM_011524381.3	c.323A>G	p.His108Arg	missense_variant	Exon 4 of 10		XP_011522683.2
EFCAB3	XM_011524380.2	c.257A>G	p.His86Arg	missense_variant	Exon 4 of 10		XP_011522682.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFCAB3	ENST00000305286.8	c.257A>G	p.His86Arg	missense_variant	Exon 4 of 10	1	NM_173503.4	ENSP00000302649.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460640 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726632

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33474

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44702

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26102

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39664

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86042

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53374

Gnomad4 NFE exome AF: 0.00000540 AC: 6 AN: 1111178

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60344

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.413A>G (p.H138R) alteration is located in exon 6 (coding exon 6) of the EFCAB3 gene. This alteration results from a A to G substitution at nucleotide position 413, causing the histidine (H) at amino acid position 138 to be replaced by an arginine (R). 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	0.074
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	10
DANN	Benign	0.58
DEOGEN2	Benign	0.0015	.;T;.;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.53	T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.27	.;N;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.22	T;T;T;T
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.0030, 0.0010	.;B;B;.
Vest4		0.27
MutPred		0.34		.;Loss of ubiquitination at K85 (P = 0.0547);Loss of ubiquitination at K85 (P = 0.0547);Loss of ubiquitination at K85 (P = 0.0547);
MVP		0.76
MPC		0.18
ClinPred		0.083	T
GERP RS		2.6
Varity_R		0.043
gMVP		0.17
Mutation Taster		=93/7	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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-60469288;