rs180724802

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003923.3(FOXH1):c.47C>T(p.Ser16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000409 in 1,422,416 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S16S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

FOXH1
NM_003923.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.63

Publications

2 publications found

Variant links:

Genes affected

FOXH1 (HGNC:3814): (forkhead box H1) FOXH1 encodes a human homolog of Xenopus forkhead activin signal transducer-1. FOXH1 protein binds SMAD2 and activates an activin response element via binding the DNA motif TGT(G/T)(T/G)ATT. [provided by RefSeq, Jul 2008]

FOXH1 Gene-Disease associations (from GenCC):

congenital heart malformation
Inheritance: Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine

FOXH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006274283).

BP6

Variant 8-144475710-G-A is Benign according to our data. Variant chr8-144475710-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259200.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00218 (332/152292) while in subpopulation AFR AF = 0.00775 (322/41562). AF 95% confidence interval is 0.00705. There are 2 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXH1	NM_003923.3 link	c.47C>T	p.Ser16Leu	missense_variant	Exon 1 of 3	ENST00000377317.5	NP_003914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXH1	ENST00000377317.5 link	c.47C>T	p.Ser16Leu	missense_variant	Exon 1 of 3	1	NM_003923.3	ENSP00000366534.4
FOXH1	ENST00000525197.1 link	n.114C>T		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

332

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00777

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000808

AC:

AN:

70532

AF XY:

0.000627

show subpopulations

Gnomad AFR exome

AF:

0.00785

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000313

Gnomad OTH exome

AF:

0.000573

GnomAD4 exome

AF:

0.000197

AC:

250

AN:

1270124

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

AN XY:

613946

show subpopulations

African (AFR)

AF:

0.00795

AC:

221

AN:

27812

American (AMR)

AF:

0.000355

AC:

AN:

14088

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18038

East Asian (EAS)

AF:

0.00

AC:

AN:

33188

South Asian (SAS)

AF:

0.00

AC:

AN:

55654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5066

European-Non Finnish (NFE)

AF:

0.00000392

AC:

AN:

1019810

Other (OTH)

AF:

0.000385

AC:

AN:

51986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00218

AC:

332

AN:

152292

Hom.:

Cov.:

AF XY:

0.00224

AC XY:

167

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00775

AC:

322

AN:

41562

American (AMR)

AF:

0.000457

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.000882

Hom.:

Bravo

AF:

0.00257

ESP6500AA

AF:

0.00611

AC:

ESP6500EA

AF:

0.000238

AC:

ExAC

AF:

0.000470

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Holoprosencephaly sequence

Benign:2

Nov 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Uncertain:1

Nov 08, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient with a congenital heart defect in published literature (Roessler et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18538293) -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0063

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.4

PhyloP100

1.6

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.4

REVEL

Benign

0.17

Sift

Uncertain

0.016

Sift4G

Benign

0.39

Polyphen

0.0070

Vest4

0.080

MVP

0.93

MPC

0.026

ClinPred

0.027

GERP RS

3.5

PromoterAI

-0.031

Neutral

(source)

Varity_R

0.13

gMVP

0.47

Mutation Taster

=98/2

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over