9-20720435-G-C

Variant names:

• chr9-20720435-G-C
• rs143009945
• NM_001375567.1:c.188G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001375567.1(FOCAD):​c.188G>C​(p.Arg63Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R63Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: FOCAD NM_001375567.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.20
• Publications: 7 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOCAD	NM_001375567.1	c.188G>C	p.Arg63Pro	missense_variant	Exon 4 of 44	ENST00000338382.11	NP_001362496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOCAD	ENST00000338382.11	c.188G>C	p.Arg63Pro	missense_variant	Exon 4 of 44	5	NM_001375567.1	ENSP00000344307.6
FOCAD	ENST00000380249.5	c.188G>C	p.Arg63Pro	missense_variant	Exon 6 of 46	1		ENSP00000369599.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251348 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

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: 0.00000479 AC: 7 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111964

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-1.1	T
PhyloP100		4.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.28
Sift	Benign	0.063	T;T
Sift4G	Uncertain	0.0080	D;D
Vest4		0.86
MutPred		0.49		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.33
MPC		0.023
ClinPred		0.91	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.82
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs143009945; hg19: chr9-20720434;