8-144474962-G-C

Variant names:

• chr8-144474962-G-C
• NM_003923.3:c.374C>G
• FOXH1 p.Thr125Ser

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003923.3(FOXH1):​c.374C>G​(p.Thr125Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: FOXH1 NM_003923.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.47
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003923.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXH1	NM_003923.3	MANE Select	c.374C>G	p.Thr125Ser	missense	Exon 3 of 3	NP_003914.1	O75593

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXH1	ENST00000377317.5	TSL:1 MANE Select	c.374C>G	p.Thr125Ser	missense	Exon 3 of 3	ENSP00000366534.4	O75593
	FOXH1	ENST00000935088.1		c.365C>G	p.Thr122Ser	missense	Exon 3 of 3	ENSP00000605147.1
	FOXH1	ENST00000935090.1		c.362C>G	p.Thr121Ser	missense	Exon 3 of 3	ENSP00000605149.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.5	L
PhyloP100		2.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.51
Sift	Benign	0.084	T
Sift4G	Benign	0.49	T
Varity_R		0.11
gMVP		0.48
Mutation Taster		=55/45	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr8-145700345;