7-4682435-C-G

Variant names:

• chr7-4682435-C-G
• rs760812037
• NM_001037165.2:c.127C>G

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.127C>G​(p.Pro43Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 145,898 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P43S) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000069 (0 hom., cov: 31)
• Consequence: FOXK1 NM_001037165.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• 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=0.11149275).

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.127C>G	p.Pro43Ala	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.127C>G	p.Pro43Ala	missense	Exon 1 of 9	ENSP00000328720.4	P85037-1
	FOXK1	ENST00000937603.1		c.127C>G	p.Pro43Ala	missense	Exon 1 of 8	ENSP00000607662.1

Frequencies

GnomAD3 genomes AF: 0.00000685 AC: 1 AN: 145898 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000685 AC: 1 AN: 145898 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 70952

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000245 AC: 1 AN: 40768

American (AMR) AF: 0.00 AC: 0 AN: 14688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 5046

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65712

Other (OTH) AF: 0.00 AC: 0 AN: 2000

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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	0.046
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	9.1
DANN	Benign	0.68
DEOGEN2	Benign	0.044	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.27	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.29
Sift	Benign	0.69	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.23		Loss of glycosylation at P43 (P = 0.0041)
MVP		0.50
MPC		1.8
ClinPred		0.049	T
GERP RS		-1.7
PromoterAI		0.053	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.019
gMVP		0.13
Mutation Taster		=93/7	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: rs760812037; hg19: chr7-4722066;