Genetic Variant NM_001375567.1:c.60T>A (chr9-20717796-T-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001375567.1(FOCAD):c.60T>A(p.Ala20Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,610,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

FOCAD
NM_001375567.1 splice_region, synonymous

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.308

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOCAD	NM_001375567.1 link	c.60T>A	p.Ala20Ala	splice_region_variant, synonymous_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.60T>A	p.Ala20Ala	splice_region_variant, synonymous_variant	Exon 3 of 44	5	NM_001375567.1	ENSP00000344307.6		Q5VW36
FOCAD	ENST00000380249.5 link	c.60T>A	p.Ala20Ala	splice_region_variant, synonymous_variant	Exon 5 of 46	1		ENSP00000369599.1		Q5VW36

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1458624

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725778

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.00

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26080

East Asian (EAS)

AF:

0.00

AC:

AN:

39540

South Asian (SAS)

AF:

0.00

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1110466

Other (OTH)

AF:

0.0000166

AC:

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 20 of the FOCAD mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FOCAD protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FOCAD-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.89

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.89

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_001375567.1:c.60T>A

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