dbSNP rs7833404: FOXH1:p.Leu359Leu (chr8-144474259-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003923.3(FOXH1):c.1077G>A(p.Leu359Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,585,730 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 61 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 58 hom. )

Consequence

FOXH1
NM_003923.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.955

Publications

4 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 8-144474259-C-T is Benign according to our data. Variant chr8-144474259-C-T is described in ClinVar as Benign. ClinVar VariationId is 137397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.955 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0504 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXH1	NM_003923.3	MANE Select	c.1077G>A	p.Leu359Leu	synonymous	Exon 3 of 3	NP_003914.1	O75593
KIFC2	NM_001369769.2	MANE Select	c.*870C>T		downstream_gene	N/A	NP_001356698.1	A0A2R8YEU8
KIFC2	NM_145754.5		c.*809C>T		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.1077G>A	p.Leu359Leu	synonymous	Exon 3 of 3	ENSP00000366534.4	O75593
FOXH1	ENST00000935088.1		c.1068G>A	p.Leu356Leu	synonymous	Exon 3 of 3	ENSP00000605147.1
FOXH1	ENST00000935090.1		c.1065G>A	p.Leu355Leu	synonymous	Exon 3 of 3	ENSP00000605149.1

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2286

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0517

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00700

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00419

AC:

945

AN:

225332

AF XY:

0.00312

show subpopulations

Gnomad AFR exome

AF:

0.0560

Gnomad AMR exome

AF:

0.00225

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000178

Gnomad OTH exome

AF:

0.00313

GnomAD4 exome

AF:

0.00152

AC:

2183

AN:

1433398

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

939

AN XY:

709876

show subpopulations

African (AFR)

AF:

0.0525

AC:

1724

AN:

32864

American (AMR)

AF:

0.00287

AC:

122

AN:

42522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23798

East Asian (EAS)

AF:

0.00

AC:

AN:

39502

South Asian (SAS)

AF:

0.000122

AC:

AN:

81688

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50944

Middle Eastern (MID)

AF:

0.00267

AC:

AN:

5620

European-Non Finnish (NFE)

AF:

0.0000975

AC:

107

AN:

1097364

Other (OTH)

AF:

0.00347

AC:

205

AN:

59096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

115

230

345

460

575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.0150

AC:

2286

AN:

152332

Hom.:

Cov.:

AF XY:

0.0145

AC XY:

1083

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0515

AC:

2142

AN:

41564

American (AMR)

AF:

0.00699

AC:

107

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68018

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

114

228

343

457

571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0116

Hom.:

Bravo

AF:

0.0171

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Holoprosencephaly sequence (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

2.1

(source)

DANN

Benign

0.82

PhyloP100

-0.95

Mutation Taster

=100/0

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