rs138792321

Positions:

• chr8-144474287-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_003923.3(FOXH1):​c.1049A>G​(p.Asp350Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000365 in 1,604,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D350D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: FOXH1 NM_003923.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.577

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.096247524).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000434 (66/152240) while in subpopulation AMR AF= 0.00203 (31/15304). AF 95% confidence interval is 0.00147. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 66 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXH1	NM_003923.3	c.1049A>G	p.Asp350Gly	missense_variant	3/3	ENST00000377317.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXH1	ENST00000377317.5	c.1049A>G	p.Asp350Gly	missense_variant	3/3	1	NM_003923.3	P1

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152122 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000243 AC: 59 AN: 242722 Hom.: 0 AF XY: 0.000242 AC XY: 32 AN XY: 132192

Gnomad AFR exome AF: 0.0000650

Gnomad AMR exome AF: 0.000615

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000313

Gnomad OTH exome AF: 0.000507

GnomAD4 exome AF: 0.000357 AC: 519 AN: 1452552 Hom.: 0 Cov.: 35 AF XY: 0.000356 AC XY: 257 AN XY: 721562

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000656

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000410

Gnomad4 OTH exome AF: 0.000583

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74432

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000468

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000354 AC: 3

ExAC AF: 0.000207 AC: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holoprosencephaly sequence Uncertain:2

Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 350 of the FOXH1 protein (p.Asp350Gly). This variant is present in population databases (rs138792321, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with holoprosencephaly and/or tetralogy of Fallot (PMID: 18538293). ClinVar contains an entry for this variant (Variation ID: 458508). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FOXH1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20497191, 18538293) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 30, 2020	The FOXH1 c.1049A>G; p.Asp350Gly variant (rs138792321) is reported in the literature in two individuals affected with holoprosencephaly, one of whom was homozygous for the variant, and another individual with tetralogy of Fallot (Roessler 2008). This variant is found in the general population with an overall allele frequency of 0.02% (67/274084 alleles) in the Genome Aggregation Database. The aspartate at codon 350 is weakly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. This variant also exhibited decreased ability to rescue zebrafish morphant defects, however the extent and significance of such decreased activity is unclear. Due to limited information, the clinical significance of the p.Asp350Gly variant is uncertain at this time. References: Roessler et al., Reduced NODAL signaling strength via mutation of several pathway members including FOXH1 is linked to human heart defects and holoprosencephaly. Am J Hum Genet. 2008 Jul;83(1):18-29. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.054
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.096	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.093	T
Polyphen		0.062	B
Vest4		0.44
MVP		0.92
MPC		0.083
ClinPred		0.083	T
GERP RS		5.3
Varity_R		0.29
gMVP		0.54

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: rs138792321; hg19: chr8-145699670;