dbSNP rs4977881: FOCAD:p.Lys1668Gln (chr9-20988427-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_017794.5(FOCAD):c.5002A>C(p.Lys1668Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. K1668N) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOCAD
NM_017794.5 missense, splice_region

Scores

Splicing: ADA: 0.0003021

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.09888178).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017794.5. 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>C	p.Lys1668Gln	missense splice_region	Exon 41 of 44	NP_001362496.1
FOCAD	NM_017794.5		c.5002A>C	p.Lys1668Gln	missense splice_region	Exon 43 of 46	NP_060264.4
FOCAD	NM_001375568.1		c.4897A>C	p.Lys1633Gln	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>C	p.Lys1668Gln	missense splice_region	Exon 41 of 44	ENSP00000344307.6
FOCAD	ENST00000380249.5	TSL:1	c.5002A>C	p.Lys1668Gln	missense splice_region	Exon 43 of 46	ENSP00000369599.1
FOCAD	ENST00000605086.5	TSL:1	n.3472A>C		splice_region non_coding_transcript_exon	Exon 29 of 32

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1418142

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

708122

African (AFR)

AF:

0.00

AC:

AN:

32490

American (AMR)

AF:

0.00

AC:

AN:

42772

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25756

East Asian (EAS)

AF:

0.00

AC:

AN:

39044

South Asian (SAS)

AF:

0.00

AC:

AN:

84432

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1075970

Other (OTH)

AF:

0.00

AC:

AN:

58772

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0024

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.44

M_CAP

Benign

0.011

MetaRNN

Benign

0.099

MetaSVM

Benign

-1.0

PhyloP100

1.6

PrimateAI

Benign

0.37

PROVEAN

Benign

0.38

REVEL

Benign

0.067

Sift

Benign

0.53

Sift4G

Benign

0.19

Vest4

0.13

MutPred

0.17

Loss of ubiquitination at K1668 (P = 0.0148)

MVP

0.28

MPC

0.0057

ClinPred

0.32

GERP RS

5.3

gMVP

0.28

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00030

dbscSNV1_RF

Benign

0.012

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over