NM_001375567.1:c.5002A>C

Variant names:

• chr9-20988427-A-C
• rs4977881
• NM_001375567.1:c.5002A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_001375567.1(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. 16/21 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. K1668E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOCAD NM_001375567.1 missense, splice_region
• Scores: Splicing: ADA: 0.0003021
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64

Genes affected

FOCAD (HGNC:23377): (focadhesin) Located in focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 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 Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.09888178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOCAD	NM_001375567.1	c.5002A>C	p.Lys1668Gln	missense_variant, splice_region_variant	Exon 41 of 44	ENST00000338382.11	NP_001362496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOCAD	ENST00000338382.11	c.5002A>C	p.Lys1668Gln	missense_variant, splice_region_variant	Exon 41 of 44	5	NM_001375567.1	ENSP00000344307.6
FOCAD	ENST00000380249.5	c.5002A>C	p.Lys1668Gln	missense_variant, splice_region_variant	Exon 43 of 46	1		ENSP00000369599.1
FOCAD	ENST00000605086.5	n.3472A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 29 of 32	1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1418142 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 708122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.0024	.;.;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.44	.;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.099	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.38	N;N;.
REVEL	Benign	0.067
Sift	Benign	0.53	T;T;.
Sift4G	Benign	0.19	T;T;T
Vest4		0.13
MutPred		0.17		Loss of ubiquitination at K1668 (P = 0.0148);Loss of ubiquitination at K1668 (P = 0.0148);.;
MVP		0.28
MPC		0.0057
ClinPred		0.32	T
GERP RS		5.3
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs4977881; hg19: chr9-20988426;