NM_003923.3:c.373A>T

Variant names:

• chr8-144474963-T-A
• rs112028242
• NM_003923.3:c.373A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003923.3(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 NM_003923.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.372
• Publications: 4 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 196368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0752 is higher than 0.05.

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.373A>T	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.373A>T	p.Thr125Ser	missense	Exon 3 of 3	ENSP00000366534.4	O75593
	FOXH1	ENST00000935088.1		c.364A>T	p.Thr122Ser	missense	Exon 3 of 3	ENSP00000605147.1
	FOXH1	ENST00000935090.1		c.361A>T	p.Thr121Ser	missense	Exon 3 of 3	ENSP00000605149.1

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

GnomAD2 exomes AF: 0.00572 AC: 1319 AN: 230720 AF XY: 0.00407

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 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

African (AFR) AF: 0.0849 AC: 2831 AN: 33364

American (AMR) AF: 0.00440 AC: 195 AN: 44294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25978

East Asian (EAS) AF: 0.00 AC: 0 AN: 39466

South Asian (SAS) AF: 0.000164 AC: 14 AN: 85604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50424

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5754

European-Non Finnish (NFE) AF: 0.0000910 AC: 101 AN: 1110424

Other (OTH) AF: 0.00532 AC: 320 AN: 60108

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

African (AFR) AF: 0.0774 AC: 3215 AN: 41528

American (AMR) AF: 0.00758 AC: 116 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68010

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Holoprosencephaly sequence (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.37
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
Mutation Taster		=77/23	polymorphism (auto)

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

Other links and lift over

dbSNP: rs112028242; hg19: chr8-145700346;