Genetic Variant FOCAD:p.Lys1668Glu (chr9-20988427-A-G) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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 Uncertain significance in ClinVar. 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

Publications

31 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: Benign. The variant received -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-20988429-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1701018.Status of the report is no_assertion_criteria_provided, 0 stars.

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 VariationId 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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FOCAD	NM_001375567.1	MANE Select	c.5002A>G	p.Lys1668Glu	missense splice_region	Exon 41 of 44	NP_001362496.1
FOCAD	NM_017794.5		c.5002A>G	p.Lys1668Glu	missense splice_region	Exon 43 of 46	NP_060264.4
FOCAD	NM_001375568.1		c.4897A>G	p.Lys1633Glu	missense splice_region	Exon 40 of 43	NP_001362497.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FOCAD	ENST00000338382.11	TSL:5 MANE Select	c.5002A>G	p.Lys1668Glu	missense splice_region	Exon 41 of 44	ENSP00000344307.6
FOCAD	ENST00000380249.5	TSL:1	c.5002A>G	p.Lys1668Glu	missense splice_region	Exon 43 of 46	ENSP00000369599.1
FOCAD	ENST00000605086.5	TSL:1	n.3472A>G		splice_region non_coding_transcript_exon	Exon 29 of 32

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

GnomAD2 exomes

AF:

0.742

AC:

182056

AN:

245224

AF XY:

0.736

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 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

African (AFR)

AF:

0.782

AC:

25364

AN:

32430

American (AMR)

AF:

0.711

AC:

30354

AN:

42706

Ashkenazi Jewish (ASJ)

AF:

0.749

AC:

19263

AN:

25720

East Asian (EAS)

AF:

0.913

AC:

35639

AN:

39030

South Asian (SAS)

AF:

0.675

AC:

56889

AN:

84274

European-Finnish (FIN)

AF:

0.741

AC:

39389

AN:

53176

Middle Eastern (MID)

AF:

0.666

AC:

3778

AN:

5676

European-Non Finnish (NFE)

AF:

0.725

AC:

776735

AN:

1072080

Other (OTH)

AF:

0.737

AC:

43178

AN:

58622

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

11748

23496

35243

46991

58739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19078

38156

57234

76312

95390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.751

AC:

113730

AN:

151412

Hom.:

42990

Cov.:

AF XY:

0.753

AC XY:

55712

AN XY:

73952

show subpopulations

African (AFR)

AF:

0.791

AC:

32653

AN:

41286

American (AMR)

AF:

0.735

AC:

11221

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.745

AC:

2584

AN:

3470

East Asian (EAS)

AF:

0.943

AC:

4796

AN:

5088

South Asian (SAS)

AF:

0.676

AC:

3236

AN:

4784

European-Finnish (FIN)

AF:

0.739

AC:

7735

AN:

10466

Middle Eastern (MID)

AF:

0.652

AC:

189

AN:

290

European-Non Finnish (NFE)

AF:

0.727

AC:

49228

AN:

67756

Other (OTH)

AF:

0.729

AC:

1537

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1349

2698

4047

5396

6745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

850

1700

2550

3400

4250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.739

Hom.:

102139

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

FOCAD-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

7.2

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.0020

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.25

MetaRNN

Benign

8.3e-7

MetaSVM

Benign

-0.97

PhyloP100

1.6

PrimateAI

Benign

0.38

PROVEAN

Benign

0.80

REVEL

Benign

0.11

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.063

MPC

0.0051

ClinPred

0.0034

GERP RS

5.3

gMVP

0.29

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over