NM_012184.5:c.37C>G

Variant names:

• chr2-113499293-C-G
• rs749595863
• NM_012184.5:c.37C>G

Variant summary

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

The NM_012184.5(FOXD4L1):​c.37C>G​(p.Pro13Ala) variant causes a missense 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. 16/22 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: 0.0000028 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXD4L1 NM_012184.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.822
• Publications: 0 publications found

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]

ENSG00000304550 (HGNC:):

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=0.09333712).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012184.5. 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
	FOXD4L1	NM_012184.5	MANE Select	c.37C>G	p.Pro13Ala	missense	Exon 1 of 1	NP_036316.1	Q9NU39

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXD4L1	ENST00000306507.7	TSL:6 MANE Select	c.37C>G	p.Pro13Ala	missense	Exon 1 of 1	ENSP00000302756.5	Q9NU39
	ENSG00000304550	ENST00000804501.1		n.691+2666G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000250 AC: 6 AN: 239814 AF XY: 0.0000153

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000192

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000275 AC: 4 AN: 1452308 Hom.: 1 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 722884

African (AFR) AF: 0.00 AC: 0 AN: 33334

American (AMR) AF: 0.0000912 AC: 4 AN: 43836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39500

South Asian (SAS) AF: 0.00 AC: 0 AN: 85824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106344

Other (OTH) AF: 0.00 AC: 0 AN: 59916

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	0.0020	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.093	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.82
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.14
Sift	Benign	0.055	T
Sift4G	Benign	0.39	T
Polyphen		0.39	B
Vest4		0.11
MutPred		0.21		Gain of MoRF binding (P = 0.0211)
MVP		0.66
ClinPred		0.17	T
GERP RS		2.7
Varity_R		0.064
gMVP		0.10
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs749595863; hg19: chr2-114256870;