rs144830740

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003923.3(FOXH1):c.338G>C(p.Ser113Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00576 in 1,606,692 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0059 ( 37 hom. )

Consequence

FOXH1
NM_003923.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.0440

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009800464).

BP6

Variant 8-144474998-C-G is Benign according to our data. Variant chr8-144474998-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 94385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0045 (685/152338) while in subpopulation NFE AF = 0.00845 (575/68020). AF 95% confidence interval is 0.00788. There are 1 homozygotes in GnomAd4. There are 280 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 37 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXH1	NM_003923.3 link	c.338G>C	p.Ser113Thr	missense_variant	Exon 3 of 3	ENST00000377317.5	NP_003914.1	O75593

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXH1	ENST00000377317.5 link	c.338G>C	p.Ser113Thr	missense_variant	Exon 3 of 3	1	NM_003923.3	ENSP00000366534.4		O75593
FOXH1	ENST00000525197.1 link	n.367G>C		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.00450

AC:

685

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00845

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00395

AC:

911

AN:

230876

AF XY:

0.00403

show subpopulations

Gnomad AFR exome

AF:

0.000802

Gnomad AMR exome

AF:

0.000539

Gnomad ASJ exome

AF:

0.00711

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00133

Gnomad NFE exome

AF:

0.00753

Gnomad OTH exome

AF:

0.00297

GnomAD4 exome

AF:

0.00589

AC:

8563

AN:

1454354

Hom.:

Cov.:

AF XY:

0.00590

AC XY:

4266

AN XY:

722986

show subpopulations

African (AFR)

AF:

0.000991

AC:

AN:

33308

American (AMR)

AF:

0.000658

AC:

AN:

44058

Ashkenazi Jewish (ASJ)

AF:

0.00562

AC:

146

AN:

25964

East Asian (EAS)

AF:

0.00

AC:

AN:

39342

South Asian (SAS)

AF:

0.0000235

AC:

AN:

85196

European-Finnish (FIN)

AF:

0.00217

AC:

111

AN:

51204

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00723

AC:

8018

AN:

1109468

Other (OTH)

AF:

0.00371

AC:

223

AN:

60062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

573

1147

1720

2294

2867

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

260

520

780

1040

1300

<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:

0.00450

AC:

685

AN:

152338

Hom.:

Cov.:

AF XY:

0.00376

AC XY:

280

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000818

AC:

AN:

41576

American (AMR)

AF:

0.00105

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00845

AC:

575

AN:

68020

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

104

138

173

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:

0.00697

Hom.:

Bravo

AF:

0.00396

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.000684

AC:

ESP6500EA

AF:

0.00666

AC:

ExAC

AF:

0.00424

AC:

512

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 24, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 18538293, 25093829, 32859249) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FOXH1: BS1, BS2 -

not specified

Benign:4

Aug 09, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 23, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Holoprosencephaly sequence

Benign:2

Mar 06, 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. -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

0.13

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

Eigen

Benign

0.049

Eigen_PC

Benign

0.024

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.64

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.0098

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

1.0

PhyloP100

0.044

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.92

REVEL

Pathogenic

0.66

Sift

Benign

0.13

Sift4G

Benign

0.17

Polyphen

0.99

Vest4

0.26

MVP

0.93

MPC

0.10

ClinPred

0.029

GERP RS

3.4

Varity_R

0.11

gMVP

0.41

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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