7-4682534-G-A

Variant names:

• chr7-4682534-G-A
• rs1779764805
• NM_001037165.2:c.226G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001037165.2(FOXK1):​c.226G>A​(p.Gly76Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000102 in 981,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: FOXK1 NM_001037165.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0400
• Publications: 0 publications found

Genes affected

FOXK1 (HGNC:23480): (forkhead box K1) Enables 14-3-3 protein binding activity; DNA-binding transcription repressor activity, RNA polymerase II-specific; and transcription cis-regulatory region binding activity. Involved in several processes, including cellular glucose homeostasis; negative regulation of autophagy; and regulation of transcription, DNA-templated. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.114770204).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037165.2. 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
	FOXK1	NM_001037165.2	MANE Select	c.226G>A	p.Gly76Arg	missense	Exon 1 of 9	NP_001032242.1	P85037-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXK1	ENST00000328914.5	TSL:2 MANE Select	c.226G>A	p.Gly76Arg	missense	Exon 1 of 9	ENSP00000328720.4	P85037-1
	FOXK1	ENST00000937603.1		c.226G>A	p.Gly76Arg	missense	Exon 1 of 8	ENSP00000607662.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000102 AC: 1 AN: 981186 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 463498

African (AFR) AF: 0.0000515 AC: 1 AN: 19408

American (AMR) AF: 0.00 AC: 0 AN: 5158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9868

East Asian (EAS) AF: 0.00 AC: 0 AN: 15718

South Asian (SAS) AF: 0.00 AC: 0 AN: 18818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2370

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 858954

Other (OTH) AF: 0.00 AC: 0 AN: 36392

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Benign	0.89
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.34	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.040
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.86	N
REVEL	Benign	0.26
Sift	Benign	0.098	T
Sift4G	Benign	0.57	T
Polyphen		0.96	D
Vest4		0.20
MutPred		0.23		Gain of methylation at G76 (P = 0.0128)
MVP		0.40
MPC		2.2
ClinPred		0.22	T
GERP RS		-0.33
PromoterAI		-0.083	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.034
gMVP		0.17
Mutation Taster		=97/3	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: rs1779764805; hg19: chr7-4722165;