Genetic Variant FOXH1:p.Asp350Val (chr8-144474287-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_003923.3(FOXH1):c.1049A>T(p.Asp350Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D350G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FOXH1
NM_003923.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.577

Publications

0 publications found

Variant links:

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 links:

KIFC2 (HGNC:29530): (kinesin family member C2) Predicted to enable microtubule binding activity and microtubule motor activity. Predicted to be involved in microtubule-based movement and mitotic spindle assembly. Predicted to be located in cytoplasm. Predicted to be part of kinesin complex. Predicted to be active in microtubule cytoskeleton and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

KIFC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.752

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXH1	NM_003923.3 link	c.1049A>T	p.Asp350Val	missense_variant	Exon 3 of 3	ENST00000377317.5	NP_003914.1	O75593
KIFC2	NM_001369769.2 link	c.*898T>A		downstream_gene_variant		ENST00000645548.2	NP_001356698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXH1	ENST00000377317.5 link	c.1049A>T	p.Asp350Val	missense_variant	Exon 3 of 3	1	NM_003923.3	ENSP00000366534.4	O75593
KIFC2	ENST00000645548.2 link	c.*898T>A		downstream_gene_variant			NM_001369769.2	ENSP00000494595.1	A0A2R8YEU8
KIFC2	ENST00000301332.3 link	c.*837T>A		downstream_gene_variant		1		ENSP00000301332.2	Q96AC6-1
KIFC2	ENST00000643461.1 link	n.*85T>A		downstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1452552

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721562

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33258

American (AMR)

AF:

0.00

AC:

AN:

44236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25482

East Asian (EAS)

AF:

0.00

AC:

AN:

39594

South Asian (SAS)

AF:

0.00

AC:

AN:

85520

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51934

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1106812

Other (OTH)

AF:

0.00

AC:

AN:

59998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.75

MetaSVM

Uncertain

0.67

MutationAssessor

Uncertain

2.1

PhyloP100

0.58

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.4

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.017

Polyphen

0.94

Vest4

0.61

MutPred

0.51

Loss of disorder (P = 0.0457);

MVP

0.91

MPC

0.14

ClinPred

0.93

GERP RS

5.3

Varity_R

0.26

gMVP

0.59

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over