Genetic Variant EFCAB3:p.Pro272Ala (chr17-62407159-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_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

Publications

6 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06394246).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173503.4. 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
	EFCAB3	NM_173503.4	MANE Select	c.814C>G	p.Pro272Ala	missense	Exon 8 of 10	NP_775774.1
	EFCAB3	NM_001144933.2		c.970C>G	p.Pro324Ala	missense	Exon 10 of 12	NP_001138405.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EFCAB3	ENST00000305286.8	TSL:1 MANE Select	c.814C>G	p.Pro272Ala	missense	Exon 8 of 10	ENSP00000302649.3
EFCAB3	ENST00000450662.7	TSL:5	c.970C>G	p.Pro324Ala	missense	Exon 10 of 12	ENSP00000403932.2
EFCAB3	ENST00000636041.1	TSL:5	n.1199C>G		non_coding_transcript_exon	Exon 12 of 14

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

GnomAD2 exomes

AF:

0.000268

AC:

AN:

242598

AF XY:

0.000252

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 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

African (AFR)

AF:

0.00225

AC:

AN:

32926

American (AMR)

AF:

0.000329

AC:

AN:

42512

Ashkenazi Jewish (ASJ)

AF:

0.0000389

AC:

AN:

25732

East Asian (EAS)

AF:

0.0000760

AC:

AN:

39478

South Asian (SAS)

AF:

0.000514

AC:

AN:

83588

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53260

Middle Eastern (MID)

AF:

0.000700

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.000145

AC:

161

AN:

1108598

Other (OTH)

AF:

0.000300

AC:

AN:

60002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000828

AC:

126

AN:

152148

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00214

AC:

AN:

41508

American (AMR)

AF:

0.000851

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00125

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000517

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

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.066

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.80

M_CAP

Benign

0.033

MetaRNN

Benign

0.064

MetaSVM

Uncertain

0.047

MutationAssessor

Uncertain

2.6

PhyloP100

2.6

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.48

Sift

Benign

0.059

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.40

MVP

0.93

MPC

0.63

ClinPred

0.055

GERP RS

5.9

Varity_R

0.11

gMVP

0.15

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over