2-113499344-C-G

Variant names:

• chr2-113499344-C-G
• rs1335618067
• NM_012184.5:c.88C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012184.5(FOXD4L1):​c.88C>G​(p.Leu30Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,459,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: FOXD4L1 NM_012184.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0550

Genes affected

FOXD4L1 (HGNC:18521): (forkhead box D4 like 1) This gene is a member of the forkhead/winged-helix (FOX) family of transcription factors with highly conserved FOX DNA-binding domains. Members of the FOX family of transcription factors are regulators of embryogenesis and may play a role in human cancer. This gene lies in a region of chromosome 2 that surrounds the site where two ancestral chromosomes fused to form human chromosome 2. This region is duplicated elsewhere in the human genome, primarily in subtelomeric and pericentromeric locations, thus mutiple copies of this gene have been found. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19125581).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD4L1	NM_012184.5	c.88C>G	p.Leu30Val	missense_variant	Exon 1 of 1	ENST00000306507.7	NP_036316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXD4L1	ENST00000306507.7	c.88C>G	p.Leu30Val	missense_variant	Exon 1 of 1	6	NM_012184.5	ENSP00000302756.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000807 AC: 2 AN: 247692 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134526

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1459374 Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8 AN XY: 725998

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: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.88C>G (p.L30V) alteration is located in exon 1 (coding exon 1) of the FOXD4L1 gene. This alteration results from a C to G substitution at nucleotide position 88, causing the leucine (L) at amino acid position 30 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0035	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.7	L
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.21
Sift	Benign	0.25	T
Sift4G	Benign	0.95	T
Polyphen		0.99	D
Vest4		0.067
MutPred		0.23		Loss of catalytic residue at L30 (P = 0.0747);
MVP		0.84
ClinPred		0.50	D
GERP RS		2.7
Varity_R		0.072
gMVP		0.086

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

Publications

LitVar

Other links and lift over

dbSNP: rs1335618067; hg19: chr2-114256921;