NM_003923.3:c.984C>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003923.3(FOXH1):c.984C>G(p.Asp328Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,613,070 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 4 hom. )

Consequence

FOXH1
NM_003923.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.351

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 links:

KIFC2 (HGNC:29530): (kinesin family member C2) Predicted to enable microtubule binding activity and microtubule motor activity. Predicted to be involved in microtubule-based movement and mitotic spindle assembly. Predicted to be located in cytoplasm. Predicted to be part of kinesin complex. Predicted to be active in microtubule cytoskeleton and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

KIFC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009261817).

BP6

Variant 8-144474352-G-C is Benign according to our data. Variant chr8-144474352-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 281145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144474352-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00155 (236/152364) while in subpopulation AMR AF= 0.0062 (95/15314). AF 95% confidence interval is 0.00519. There are 1 homozygotes in gnomad4. There are 123 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 236 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXH1	NM_003923.3 link	c.984C>G	p.Asp328Glu	missense_variant	Exon 3 of 3	ENST00000377317.5	NP_003914.1	O75593
KIFC2	NM_001369769.2 link	c.*963G>C		downstream_gene_variant		ENST00000645548.2	NP_001356698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXH1	ENST00000377317.5 link	c.984C>G	p.Asp328Glu	missense_variant	Exon 3 of 3	1	NM_003923.3	ENSP00000366534.4	O75593
KIFC2	ENST00000645548.2 link	c.*963G>C		downstream_gene_variant			NM_001369769.2	ENSP00000494595.1	A0A2R8YEU8
KIFC2	ENST00000301332.3 link	c.*902G>C		downstream_gene_variant		1		ENSP00000301332.2	Q96AC6-1
KIFC2	ENST00000643461.1 link	n.*150G>C		downstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.00155

AC:

236

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00621

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00162

AC:

404

AN:

249478

Hom.:

AF XY:

0.00148

AC XY:

201

AN XY:

135412

show subpopulations

Gnomad AFR exome

AF:

0.000251

Gnomad AMR exome

AF:

0.00405

Gnomad ASJ exome

AF:

0.00250

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00182

Gnomad OTH exome

AF:

0.00378

GnomAD4 exome

AF:

0.00193

AC:

2826

AN:

1460706

Hom.:

Cov.:

AF XY:

0.00194

AC XY:

1413

AN XY:

726658

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.00427

Gnomad4 ASJ exome

AF:

0.00191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000650

Gnomad4 NFE exome

AF:

0.00219

Gnomad4 OTH exome

AF:

0.00171

GnomAD4 genome

AF:

0.00155

AC:

236

AN:

152364

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

123

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00620

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00156

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00106

Hom.:

Bravo

AF:

0.00188

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00136

AC:

165

EpiCase

AF:

0.00191

EpiControl

AF:

0.00249

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

not specified

Benign:2

Aug 02, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Oct 14, 2015

Eurofins Ntd Llc (ga)

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. -

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Uncertain

0.13

CADD

Benign

2.1

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.53

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.0093

MetaSVM

Uncertain

0.63

MutationAssessor

Uncertain

2.1

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.91

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0090

Polyphen

0.96

Vest4

0.23

MutPred

0.74

Gain of solvent accessibility (P = 0.3089);

MVP

0.91

MPC

0.21

ClinPred

0.075

GERP RS

-2.3

Varity_R

0.71

gMVP

0.67

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