rs112028242

Positions:

• chr8-144474963-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000377317.5(FOXH1):​c.373A>T​(p.Thr125Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,607,644 control chromosomes in the GnomAD database, including 278 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (137 hom., cov: 34)
  • Exomes 𝑓: 0.0024 (141 hom.)
• Consequence: FOXH1 ENST00000377317.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.372

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=0.003989786).
• BP6: Variant 8-144474963-T-A is Benign according to our data. Variant chr8-144474963-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 196368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144474963-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXH1	NM_003923.3	c.373A>T	p.Thr125Ser	missense_variant	3/3	ENST00000377317.5	NP_003914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXH1	ENST00000377317.5	c.373A>T	p.Thr125Ser	missense_variant	3/3	1	NM_003923.3	ENSP00000366534	P1
FOXH1	ENST00000525197.1	n.402A>T		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3365 AN: 152110 Hom.: 134 Cov.: 34

Gnomad AFR AF: 0.0773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00572 AC: 1319 AN: 230720 Hom.: 57 AF XY: 0.00407 AC XY: 516 AN XY: 126930

Gnomad AFR exome AF: 0.0836

Gnomad AMR exome AF: 0.00398

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00209

GnomAD4 exome AF: 0.00239 AC: 3472 AN: 1455416 Hom.: 141 Cov.: 35 AF XY: 0.00206 AC XY: 1493 AN XY: 723760

Gnomad4 AFR exome AF: 0.0849

Gnomad4 AMR exome AF: 0.00440

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000164

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000910

Gnomad4 OTH exome AF: 0.00532

GnomAD4 genome AF: 0.0222 AC: 3380 AN: 152228 Hom.: 137 Cov.: 34 AF XY: 0.0211 AC XY: 1569 AN XY: 74442

Gnomad4 AFR AF: 0.0774

Gnomad4 AMR AF: 0.00758

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00339 Hom.: 9

Bravo AF: 0.0255

ESP6500AA AF: 0.0733 AC: 319

ESP6500EA AF: 0.000938 AC: 8

ExAC AF: 0.00684 AC: 824

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 17, 2014	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2020	- -

Holoprosencephaly sequence Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	0.072
Eigen_PC	Benign	0.081
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0040	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.45
Sift	Benign	0.084	T
Sift4G	Benign	0.49	T
Polyphen		1.0	D
Vest4		0.30
MutPred		0.49		Gain of relative solvent accessibility (P = 0.0249);
MVP		0.95
MPC		0.20
ClinPred		0.031	T
GERP RS		3.5
Varity_R		0.086
gMVP		0.48

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

Other links and lift over

dbSNP: rs112028242; hg19: chr8-145700346;