9-20988427-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBA1

The NM_001375567.1(FOCAD):c.5002A>G(p.Lys1668Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 1,565,126 control chromosomes in the GnomAD database, including 420,285 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1668N) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.75 ( 42990 hom., cov: 26)

Exomes 𝑓: 0.73 ( 377295 hom. )

Consequence

FOCAD
NM_001375567.1 missense, splice_region

Scores

Splicing: ADA: 0.0001322

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.64

Variant links:

Genes affected

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

FOCAD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-20988429-G-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=8.336058E-7).

BP6

Variant 9-20988427-A-G is Benign according to our data. Variant chr9-20988427-A-G is described in ClinVar as [Benign]. Clinvar id is 402873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOCAD	NM_001375567.1 link	c.5002A>G	p.Lys1668Glu	missense_variant, splice_region_variant	Exon 41 of 44	ENST00000338382.11	NP_001362496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOCAD	ENST00000338382.11 link	c.5002A>G	p.Lys1668Glu	missense_variant, splice_region_variant	Exon 41 of 44	5	NM_001375567.1	ENSP00000344307.6	Q5VW36
FOCAD	ENST00000380249.5 link	c.5002A>G	p.Lys1668Glu	missense_variant, splice_region_variant	Exon 43 of 46	1		ENSP00000369599.1	Q5VW36
FOCAD	ENST00000605086.5 link	n.3472A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 29 of 32	1

Frequencies

GnomAD3 genomes

AF:

0.751

AC:

113641

AN:

151296

Hom.:

42951

Cov.:

show subpopulations

Gnomad AFR

AF:

0.791

Gnomad AMI

AF:

0.610

Gnomad AMR

AF:

0.736

Gnomad ASJ

AF:

0.745

Gnomad EAS

AF:

0.943

Gnomad SAS

AF:

0.676

Gnomad FIN

AF:

0.739

Gnomad MID

AF:

0.660

Gnomad NFE

AF:

0.726

Gnomad OTH

AF:

0.728

GnomAD3 exomes

AF:

0.742

AC:

182056

AN:

245224

Hom.:

68131

AF XY:

0.736

AC XY:

97908

AN XY:

132958

show subpopulations

Gnomad AFR exome

AF:

0.793

Gnomad AMR exome

AF:

0.707

Gnomad ASJ exome

AF:

0.752

Gnomad EAS exome

AF:

0.948

Gnomad SAS exome

AF:

0.676

Gnomad FIN exome

AF:

0.740

Gnomad NFE exome

AF:

0.730

Gnomad OTH exome

AF:

0.727

GnomAD4 exome

AF:

0.729

AC:

1030589

AN:

1413714

Hom.:

377295

Cov.:

AF XY:

0.727

AC XY:

513039

AN XY:

706032

show subpopulations

Gnomad4 AFR exome

AF:

0.782

Gnomad4 AMR exome

AF:

0.711

Gnomad4 ASJ exome

AF:

0.749

Gnomad4 EAS exome

AF:

0.913

Gnomad4 SAS exome

AF:

0.675

Gnomad4 FIN exome

AF:

0.741

Gnomad4 NFE exome

AF:

0.725

Gnomad4 OTH exome

AF:

0.737

GnomAD4 genome

AF:

0.751

AC:

113730

AN:

151412

Hom.:

42990

Cov.:

AF XY:

0.753

AC XY:

55712

AN XY:

73952

show subpopulations

Gnomad4 AFR

AF:

0.791

Gnomad4 AMR

AF:

0.735

Gnomad4 ASJ

AF:

0.745

Gnomad4 EAS

AF:

0.943

Gnomad4 SAS

AF:

0.676

Gnomad4 FIN

AF:

0.739

Gnomad4 NFE

AF:

0.727

Gnomad4 OTH

AF:

0.729

Alfa

AF:

0.739

Hom.:

74048

Bravo

AF:

0.752

TwinsUK

AF:

0.741

AC:

2746

ALSPAC

AF:

0.734

AC:

2829

ESP6500AA

AF:

0.788

AC:

3470

ESP6500EA

AF:

0.720

AC:

6193

ExAC

AF:

0.742

AC:

90053

Asia WGS

AF:

0.797

AC:

2773

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

FOCAD-related disorder

Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

7.2

DANN

Benign

0.30

DEOGEN2

Benign

0.0020

.;.;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.25

.;.;T

MetaRNN

Benign

8.3e-7

T;T;T

MetaSVM

Benign

-0.97

PrimateAI

Benign

0.38

PROVEAN

Benign

0.80

N;N;.

REVEL

Benign

0.11

Sift

Benign

1.0

T;T;.

Sift4G

Benign

1.0

T;T;T

Vest4

0.063

MPC

0.0051

ClinPred

0.0034

GERP RS

5.3

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00013

dbscSNV1_RF

Benign

0.042

SpliceAI score (max)

0.020

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