9-20715363-G-T

Variant names:

• chr9-20715363-G-T
• rs757339586
• NM_001375567.1:c.10G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_001375567.1(FOCAD):​c.10G>T​(p.Asp4Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000102 in 1,371,346 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: 0.000010 (0 hom.)
• Consequence: FOCAD NM_001375567.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.69
• Publications: 1 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13744605).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000102 (14/1371346) while in subpopulation AMR AF = 0.000332 (13/39122). AF 95% confidence interval is 0.000197. There are 0 homozygotes in GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375567.1. 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
	FOCAD	NM_001375567.1	MANE Select	c.10G>T	p.Asp4Tyr	missense	Exon 2 of 44	NP_001362496.1	Q5VW36
	FOCAD	NM_017794.5		c.10G>T	p.Asp4Tyr	missense	Exon 4 of 46	NP_060264.4
	FOCAD	NM_001375568.1		c.10G>T	p.Asp4Tyr	missense	Exon 2 of 43	NP_001362497.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOCAD	ENST00000338382.11	TSL:5 MANE Select	c.10G>T	p.Asp4Tyr	missense	Exon 2 of 44	ENSP00000344307.6	Q5VW36
	FOCAD	ENST00000380249.5	TSL:1	c.10G>T	p.Asp4Tyr	missense	Exon 4 of 46	ENSP00000369599.1	Q5VW36
	FOCAD	ENST00000894775.1		c.10G>T	p.Asp4Tyr	missense	Exon 3 of 45	ENSP00000564834.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000574 AC: 13 AN: 226628 AF XY: 0.0000324

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000460

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: 0.0000102 AC: 14 AN: 1371346 Hom.: 0 Cov.: 29 AF XY: 0.00000736 AC XY: 5 AN XY: 679440

African (AFR) AF: 0.00 AC: 0 AN: 31268

American (AMR) AF: 0.000332 AC: 13 AN: 39122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23906

East Asian (EAS) AF: 0.00 AC: 0 AN: 37026

South Asian (SAS) AF: 0.0000148 AC: 1 AN: 67758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5476

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1061262

Other (OTH) AF: 0.00 AC: 0 AN: 55762

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000741 AC: 9

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.2	T
PhyloP100		5.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.010	D
Vest4		0.47
MutPred		0.23		Gain of MoRF binding (P = 0.0245)
MVP		0.27
MPC		0.026
ClinPred		0.35	T
GERP RS		5.8
gMVP		0.57
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs757339586; hg19: chr9-20715362;