Genetic Variant FOCAD:p.Ala27Val (chr9-20717816-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001375567.1(FOCAD):c.80C>T(p.Ala27Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,459,978 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

FOCAD
NM_001375567.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.78

Publications

0 publications found

Variant links:

Genes affected

FOCAD (HGNC:23377): (focadhesin) Located in focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

FOCAD Gene-Disease associations (from GenCC):

liver disease, severe congenital
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

FOCAD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.362248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOCAD	NM_001375567.1 link	c.80C>T	p.Ala27Val	missense_variant	Exon 3 of 44	ENST00000338382.11	NP_001362496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOCAD	ENST00000338382.11 link	c.80C>T	p.Ala27Val	missense_variant	Exon 3 of 44	5	NM_001375567.1	ENSP00000344307.6		Q5VW36
FOCAD	ENST00000380249.5 link	c.80C>T	p.Ala27Val	missense_variant	Exon 5 of 46	1		ENSP00000369599.1		Q5VW36

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000161

AC:

AN:

247728

AF XY:

0.00000745

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.00000342

AC:

AN:

1459978

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726400

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33416

American (AMR)

AF:

0.0000895

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39566

South Asian (SAS)

AF:

0.00

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111220

Other (OTH)

AF:

0.00

AC:

AN:

60328

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.335

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Oct 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 27 of the FOCAD protein (p.Ala27Val). This variant is present in population databases (rs780873832, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FOCAD-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.87

M_CAP

Benign

0.014

MetaRNN

Benign

0.36

T;T

MetaSVM

Benign

-1.1

PhyloP100

3.8

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.10

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0080

D;D

Vest4

0.56

MutPred

0.30

Loss of ubiquitination at K30 (P = 0.1062);Loss of ubiquitination at K30 (P = 0.1062);

MVP

0.48

MPC

0.028

ClinPred

0.61

GERP RS

5.8

gMVP

0.40

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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9-20717816-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over