NM_004514.4:c.419+7G>A

Variant names:

• chr17-82520314-G-A
• rs777846814
• NM_004514.4:c.419+7G>A

Variant summary

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

The NM_004514.4(FOXK2):​c.419+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000271 in 1,107,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FOXK2 NM_004514.4 splice_region, intron
• Scores: Splicing: ADA: 0.005679
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53
• Publications: 0 publications found

Genes affected

FOXK2 (HGNC:6036): (forkhead box K2) The protein encoded by this gene contains a fork head DNA binding domain. This protein can bind to the purine-rich motifs of the HIV long terminal repeat (LTR), and to the similar purine-rich motif in the interleukin 2 (IL2) promoter. It may be involved in the regulation of viral and cellular promoter elements. [provided by RefSeq, Jul 2008]

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 (BayesDel_noAF=-0.43).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXK2	NM_004514.4	c.419+7G>A		splice_region_variant, intron_variant	Intron 1 of 8	ENST00000335255.10	NP_004505.2
FOXK2	XM_047435919.1	c.419+7G>A		splice_region_variant, intron_variant	Intron 1 of 8		XP_047291875.1
FOXK2	XM_047435920.1	c.419+7G>A		splice_region_variant, intron_variant	Intron 1 of 4		XP_047291876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXK2	ENST00000335255.10	c.419+7G>A		splice_region_variant, intron_variant	Intron 1 of 8	1	NM_004514.4	ENSP00000335677.5
FOXK2	ENST00000473637.6	n.419+7G>A		splice_region_variant, intron_variant	Intron 1 of 9	1		ENSP00000436108.2
FOXK2	ENST00000527313.6	n.331+7G>A		splice_region_variant, intron_variant	Intron 1 of 2	3
FOXK2	ENST00000570585.1	n.14+7G>A		splice_region_variant, intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000271 AC: 3 AN: 1107446 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 526024

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

African (AFR) AF: 0.00 AC: 0 AN: 22492

American (AMR) AF: 0.00 AC: 0 AN: 8036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14124

East Asian (EAS) AF: 0.00 AC: 0 AN: 25086

South Asian (SAS) AF: 0.00 AC: 0 AN: 24290

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3014

European-Non Finnish (NFE) AF: 0.00000323 AC: 3 AN: 930128

Other (OTH) AF: 0.00 AC: 0 AN: 43994

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000034), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Uncertain	0.98
PhyloP100		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0057
dbscSNV1_RF	Benign	0.022
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: rs777846814; hg19: chr17-80478190;