Genetic Variant FOXH1:p.Asp328Glu (chr8-144474352-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003923.3(FOXH1):c.984C>G(p.Asp328Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,613,070 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 4 hom. )

Consequence

FOXH1
NM_003923.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.351

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009261817).

BP6

Variant 8-144474352-G-C is Benign according to our data. Variant chr8-144474352-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 281145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00155 (236/152364) while in subpopulation AMR AF = 0.0062 (95/15314). AF 95% confidence interval is 0.00519. There are 1 homozygotes in GnomAd4. There are 123 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 Unknown gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXH1	NM_003923.3	MANE Select	c.984C>G	p.Asp328Glu	missense	Exon 3 of 3	NP_003914.1	O75593
KIFC2	NM_001369769.2	MANE Select	c.*963G>C		downstream_gene	N/A	NP_001356698.1	A0A2R8YEU8
KIFC2	NM_145754.5		c.*902G>C		downstream_gene	N/A	NP_665697.1	Q96AC6-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXH1	ENST00000377317.5	TSL:1 MANE Select	c.984C>G	p.Asp328Glu	missense	Exon 3 of 3	ENSP00000366534.4	O75593
FOXH1	ENST00000935088.1		c.975C>G	p.Asp325Glu	missense	Exon 3 of 3	ENSP00000605147.1
FOXH1	ENST00000935090.1		c.972C>G	p.Asp324Glu	missense	Exon 3 of 3	ENSP00000605149.1

Frequencies

GnomAD3 genomes

AF:

0.00155

AC:

236

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00621

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00162

AC:

404

AN:

249478

AF XY:

0.00148

show subpopulations

Gnomad AFR exome

AF:

0.000251

Gnomad AMR exome

AF:

0.00405

Gnomad ASJ exome

AF:

0.00250

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00182

Gnomad OTH exome

AF:

0.00378

GnomAD4 exome

AF:

0.00193

AC:

2826

AN:

1460706

Hom.:

Cov.:

AF XY:

0.00194

AC XY:

1413

AN XY:

726658

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.00427

AC:

191

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00191

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000650

AC:

AN:

52334

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00219

AC:

2435

AN:

1111946

Other (OTH)

AF:

0.00171

AC:

103

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

169

338

507

676

845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<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

AF:

0.00155

AC:

236

AN:

152364

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

123

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41588

American (AMR)

AF:

0.00620

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00156

AC:

106

AN:

68024

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00106

Hom.:

Bravo

AF:

0.00188

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00136

AC:

165

EpiCase

AF:

0.00191

EpiControl

AF:

0.00249

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Holoprosencephaly sequence (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Uncertain

0.13

CADD

Benign

2.1

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.53

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.0093

MetaSVM

Uncertain

0.63

MutationAssessor

Uncertain

2.1

PhyloP100

-0.35

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.91

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0090

Polyphen

0.96

Vest4

0.23

MutPred

0.74

Gain of solvent accessibility (P = 0.3089)

MVP

0.91

MPC

0.21

ClinPred

0.075

GERP RS

-2.3

Varity_R

0.71

gMVP

0.67

Mutation Taster

=79/21

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over