Genetic Variant NM_173503.4:c.814C>G (chr17-62407159-C-G) – 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_173503.4(EFCAB3):c.814C>G(p.Pro272Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,603,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P272T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00083 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

EFCAB3
NM_173503.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.60

Variant links:

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]

EFCAB3 links:

Genome browser will be placed here

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=0.06394246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFCAB3	NM_173503.4 link	c.814C>G	p.Pro272Ala	missense_variant	Exon 8 of 10	ENST00000305286.8	NP_775774.1	Q8N7B9-1
EFCAB3	NM_001144933.2 link	c.970C>G	p.Pro324Ala	missense_variant	Exon 10 of 12		NP_001138405.1	Q8N7B9-2
EFCAB3	XM_011524381.3 link	c.880C>G	p.Pro294Ala	missense_variant	Exon 8 of 10		XP_011522683.2	Q8N7B9
EFCAB3	XM_011524380.2 link	c.814C>G	p.Pro272Ala	missense_variant	Exon 8 of 10		XP_011522682.1	Q8N7B9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EFCAB3	ENST00000305286.8 link	c.814C>G	p.Pro272Ala	missense_variant	Exon 8 of 10	1	NM_173503.4	ENSP00000302649.3	Q8N7B9-1
EFCAB3	ENST00000450662.7 link	c.970C>G	p.Pro324Ala	missense_variant	Exon 10 of 12	5		ENSP00000403932.2	Q8N7B9-2
EFCAB3	ENST00000636041.1 link	n.1199C>G		non_coding_transcript_exon_variant	Exon 12 of 14	5

Frequencies

GnomAD3 genomes

AF:

0.000822

AC:

125

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000852

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000268

AC:

AN:

242598

Hom.:

AF XY:

0.000252

AC XY:

AN XY:

130922

show subpopulations

Gnomad AFR exome

AF:

0.00180

Gnomad AMR exome

AF:

0.000216

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000561

Gnomad SAS exome

AF:

0.000426

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000126

Gnomad OTH exome

AF:

0.000339

GnomAD4 exome

AF:

0.000219

AC:

318

AN:

1451814

Hom.:

Cov.:

AF XY:

0.000230

AC XY:

166

AN XY:

721824

show subpopulations

Gnomad4 AFR exome

AF:

0.00225

Gnomad4 AMR exome

AF:

0.000329

Gnomad4 ASJ exome

AF:

0.0000389

Gnomad4 EAS exome

AF:

0.0000760

Gnomad4 SAS exome

AF:

0.000514

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000145

Gnomad4 OTH exome

AF:

0.000300

GnomAD4 genome

AF:

0.000828

AC:

126

AN:

152148

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.00214

Gnomad4 AMR

AF:

0.000851

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000832

Hom.:

Bravo

AF:

0.000967

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.970C>G (p.P324A) alteration is located in exon 10 (coding exon 10) of the EFCAB3 gene. This alteration results from a C to G substitution at nucleotide position 970, causing the proline (P) at amino acid position 324 to be replaced by an alanine (A). 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

0.25

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.066

.;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.064

T;T

MetaSVM

Uncertain

0.047

MutationAssessor

Uncertain

2.6

.;M

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.0

D;D

REVEL

Uncertain

0.48

Sift

Benign

0.059

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.40

MVP

0.93

MPC

0.63

ClinPred

0.055

GERP RS

5.9

Varity_R

0.11

gMVP

0.15

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over