rs144830740

chr8-144474998-C-Gchr8-144474998-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0440

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]

ACMG classification

Verdict is Benign. Variant got -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. Variant chr8-144474998-C-G is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 685 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXH1	NM_003923.3	c.338G>C	p.Ser113Thr	missense_variant	3/3	ENST00000377317.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXH1	ENST00000377317.5	c.338G>C	p.Ser113Thr	missense_variant	3/3	1	NM_003923.3	P1
FOXH1	ENST00000525197.1	n.367G>C		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.00450 AC: 685 AN: 152220 Hom.: 1 Cov.: 33

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

GnomAD3 exomes AF: 0.00395 AC: 911 AN: 230876 Hom.: 6 AF XY: 0.00403 AC XY: 510 AN XY: 126492

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 SAS exome AF: 0.0000343

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.: 37 Cov.: 35 AF XY: 0.00590 AC XY: 4266 AN XY: 722986

Gnomad4 AFR exome AF: 0.000991

Gnomad4 AMR exome AF: 0.000658

Gnomad4 ASJ exome AF: 0.00562

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.00217

Gnomad4 NFE exome AF: 0.00723

Gnomad4 OTH exome AF: 0.00371

GnomAD4 genome AF: 0.00450 AC: 685 AN: 152338 Hom.: 1 Cov.: 33 AF XY: 0.00376 AC XY: 280 AN XY: 74498

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00845

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00697 Hom.: 1

Bravo AF: 0.00396

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.000684 AC: 3

ESP6500EA AF: 0.00666 AC: 57

ExAC AF: 0.00424 AC: 512

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	FOXH1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2020	This variant is associated with the following publications: (PMID: 18538293, 25093829, 32859249) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 09, 2013	- -

Holoprosencephaly sequence Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.049
Eigen_PC	Benign	0.024
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.0098	T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.92	N
REVEL	Pathogenic	0.66
Sift	Benign	0.13	T
Sift4G	Benign	0.17	T
Polyphen		0.99	D
Vest4		0.26
MVP		0.93
MPC		0.10
ClinPred		0.029	T
GERP RS		3.4
Varity_R		0.11
gMVP		0.41

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

LitVar

Other links and lift over

dbSNP: rs144830740; hg19: chr8-145700381;