Genetic Variant NM_012184.5:c.536C>A (chr2-113499792-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -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. 16/22 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

Publications

4 publications found

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:

ENSG00000304550 (HGNC:):

ENSG00000304550 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 VariationId is 1206045.Status of the report is criteria_provided_single_submitter, 1 stars.

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.536C>A	p.Thr179Asn	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.536C>A	p.Thr179Asn	missense	Exon 1 of 1	ENSP00000302756.5	Q9NU39
	ENSG00000304550	ENST00000804501.1		n.691+2167G>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

133212

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00128

AC:

293

AN:

228442

AF XY:

0.00137

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 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

African (AFR)

AF:

0.00411

AC:

134

AN:

32590

American (AMR)

AF:

0.0451

AC:

1737

AN:

38544

Ashkenazi Jewish (ASJ)

AF:

0.00463

AC:

119

AN:

25680

East Asian (EAS)

AF:

0.0805

AC:

2563

AN:

31856

South Asian (SAS)

AF:

0.0348

AC:

2885

AN:

82926

European-Finnish (FIN)

AF:

0.00888

AC:

452

AN:

50914

Middle Eastern (MID)

AF:

0.00536

AC:

AN:

4850

European-Non Finnish (NFE)

AF:

0.00433

AC:

4619

AN:

1066084

Other (OTH)

AF:

0.00858

AC:

493

AN:

57456

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.702

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

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

African (AFR)

AF:

0.000240

AC:

AN:

37572

American (AMR)

AF:

0.000242

AC:

AN:

12382

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3258

East Asian (EAS)

AF:

0.000623

AC:

AN:

3208

South Asian (SAS)

AF:

0.000510

AC:

AN:

3924

European-Finnish (FIN)

AF:

0.000218

AC:

AN:

9162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

60994

Other (OTH)

AF:

0.00

AC:

AN:

1824

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.242

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0125

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.0086

BayesDel_addAF

Benign

0.0027

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

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

PhyloP100

1.5

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

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over