Genetic Variant FOXD4L1:p.Thr179Asn (chr2-113499792-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_012184.5(FOXD4L1):c.536C>A(p.Thr179Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0094 ( 6446 hom. )

Failed GnomAD Quality Control

Consequence

FOXD4L1
NM_012184.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:3

Conservation

PhyloP100: 1.46

Variant links:

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]

FOXD4L1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012960285).

BP6

Variant 2-113499792-C-A is Benign according to our data. Variant chr2-113499792-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1206045.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-113499792-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXD4L1	NM_012184.5 link	c.536C>A	p.Thr179Asn	missense_variant	Exon 1 of 1	ENST00000306507.7	NP_036316.1	Q9NU39B3KVK3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXD4L1	ENST00000306507.7 link	c.536C>A	p.Thr179Asn	missense_variant	Exon 1 of 1	6	NM_012184.5	ENSP00000302756.5		Q9NU39

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

133212

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000240

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000622

Gnomad SAS

AF:

0.000509

Gnomad FIN

AF:

0.000218

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00128

AC:

293

AN:

228442

Hom.:

136

AF XY:

0.00137

AC XY:

171

AN XY:

125196

show subpopulations

Gnomad AFR exome

AF:

0.000343

Gnomad AMR exome

AF:

0.00348

Gnomad ASJ exome

AF:

0.000511

Gnomad EAS exome

AF:

0.00654

Gnomad SAS exome

AF:

0.00213

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000307

Gnomad OTH exome

AF:

0.000346

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00937

AC:

13028

AN:

1390900

Hom.:

6446

Cov.:

AF XY:

0.0103

AC XY:

7105

AN XY:

693136

show subpopulations

Gnomad4 AFR exome

AF:

0.00411

Gnomad4 AMR exome

AF:

0.0451

Gnomad4 ASJ exome

AF:

0.00463

Gnomad4 EAS exome

AF:

0.0805

Gnomad4 SAS exome

AF:

0.0348

Gnomad4 FIN exome

AF:

0.00888

Gnomad4 NFE exome

AF:

0.00433

Gnomad4 OTH exome

AF:

0.00858

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000263

AC:

AN:

133312

Hom.:

Cov.:

AF XY:

0.000249

AC XY:

AN XY:

64384

show subpopulations

Gnomad4 AFR

AF:

0.000240

Gnomad4 AMR

AF:

0.000242

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000623

Gnomad4 SAS

AF:

0.000510

Gnomad4 FIN

AF:

0.000218

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0125

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.0086

BayesDel_addAF

Benign

0.0027

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.15

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.77

M_CAP

Benign

0.041

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.47

MutationAssessor

Benign

-2.5

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

5.9

REVEL

Benign

0.23

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.15

MVP

0.45

ClinPred

0.011

GERP RS

1.3

Varity_R

0.066

gMVP

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over