chr9-20764871-T-C

Variant names:

• chr9-20764871-T-C
• rs10511687
• NM_001375567.1:c.497T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001375567.1(FOCAD):​c.497T>C​(p.Leu166Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 1,611,422 control chromosomes in the GnomAD database, including 101,775 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8890 hom., cov: 32)
  • Exomes 𝑓: 0.35 (92885 hom.)
• Consequence: FOCAD NM_001375567.1 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.10
• Publications: 29 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023242235).
• BP6: Variant 9-20764871-T-C is Benign according to our data. Variant chr9-20764871-T-C is described in ClinVar as Benign. ClinVar VariationId is 402871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

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.497T>C	p.Leu166Ser	missense splice_region	Exon 7 of 44	NP_001362496.1	Q5VW36
	FOCAD	NM_017794.5		c.497T>C	p.Leu166Ser	missense splice_region	Exon 9 of 46	NP_060264.4
	FOCAD	NM_001375568.1		c.497T>C	p.Leu166Ser	missense splice_region	Exon 7 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.497T>C	p.Leu166Ser	missense splice_region	Exon 7 of 44	ENSP00000344307.6	Q5VW36
	FOCAD	ENST00000380249.5	TSL:1	c.497T>C	p.Leu166Ser	missense splice_region	Exon 9 of 46	ENSP00000369599.1	Q5VW36
	FOCAD	ENST00000894775.1		c.497T>C	p.Leu166Ser	missense splice_region	Exon 8 of 45	ENSP00000564834.1

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50807 AN: 151928 Hom.: 8888 Cov.: 32

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.0482

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.419

Gnomad MID AF: 0.350

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.336

GnomAD2 exomes AF: 0.319 AC: 79962 AN: 250522 AF XY: 0.328

Gnomad AFR exome AF: 0.321

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.285

Gnomad EAS exome AF: 0.0419

Gnomad FIN exome AF: 0.416

Gnomad NFE exome AF: 0.355

Gnomad OTH exome AF: 0.337

GnomAD4 exome AF: 0.352 AC: 513081 AN: 1459376 Hom.: 92885 Cov.: 32 AF XY: 0.353 AC XY: 256458 AN XY: 726000

African (AFR) AF: 0.320 AC: 10691 AN: 33442

American (AMR) AF: 0.250 AC: 11165 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 7306 AN: 26096

East Asian (EAS) AF: 0.0675 AC: 2679 AN: 39674

South Asian (SAS) AF: 0.377 AC: 32435 AN: 86044

European-Finnish (FIN) AF: 0.410 AC: 21877 AN: 53318

Middle Eastern (MID) AF: 0.333 AC: 1917 AN: 5762

European-Non Finnish (NFE) AF: 0.364 AC: 404442 AN: 1110058

Other (OTH) AF: 0.341 AC: 20569 AN: 60326

GnomAD4 genome AF: 0.334 AC: 50836 AN: 152046 Hom.: 8890 Cov.: 32 AF XY: 0.334 AC XY: 24831 AN XY: 74314

African (AFR) AF: 0.322 AC: 13343 AN: 41466

American (AMR) AF: 0.277 AC: 4231 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 972 AN: 3472

East Asian (EAS) AF: 0.0483 AC: 250 AN: 5172

South Asian (SAS) AF: 0.367 AC: 1768 AN: 4820

European-Finnish (FIN) AF: 0.419 AC: 4417 AN: 10536

Middle Eastern (MID) AF: 0.342 AC: 100 AN: 292

European-Non Finnish (NFE) AF: 0.365 AC: 24786 AN: 67982

Other (OTH) AF: 0.333 AC: 705 AN: 2114

Alfa AF: 0.345 Hom.: 45883

Bravo AF: 0.320

TwinsUK AF: 0.358 AC: 1327

ALSPAC AF: 0.359 AC: 1385

ESP6500AA AF: 0.322 AC: 1420

ESP6500EA AF: 0.365 AC: 3143

ExAC AF: 0.322 AC: 39067

Asia WGS AF: 0.208 AC: 724 AN: 3478

EpiCase AF: 0.361

EpiControl AF: 0.367

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	FOCAD-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	18
DANN	Benign	0.95
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.074	N
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.96	T
PhyloP100		2.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.71	N
REVEL	Benign	0.069
Sift	Benign	1.0	T
Sift4G	Benign	0.90	T
Vest4		0.028
MPC		0.0051
ClinPred		0.0034	T
GERP RS		6.0
gMVP		0.19
Mutation Taster		=92/8	polymorphism (auto)

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: rs10511687; hg19: chr9-20764870; COSMIC: COSV58093796;