rs374587860

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_003923.3(FOXH1):c.15C>T(p.Ser5Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,414,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 0 hom. )

Consequence

FOXH1
NM_003923.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.860

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:

PPP1R16A (HGNC:14941): (protein phosphatase 1 regulatory subunit 16A) Myosin light chain kinase and phosphatase (MLCP) complexes control the phosphorylation states of regulatory myosin light chains, which is crucial for muscle and intracellular movement. MLCPs typically contain a catalytic protein phosphatase 1 (PP1c) subunit, a myosin phosphatase targeting (MYPT) subunit, and another smaller subunit. The protein encoded by this gene represents an MYPT subunit, which is responsible for directing PP1c to its intended targets. However, while the phosphorylation of other MYPT members results in PP1c inactivation, phosphorylation of the encoded protein by protein kinase A results in PP1c activation. [provided by RefSeq, Jan 2020]

PPP1R16A links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_003923.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 8-144475742-G-A is Benign according to our data. Variant chr8-144475742-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215825.

BP7

Synonymous conserved (PhyloP=-0.86 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000873 (133/152274) while in subpopulation AMR AF = 0.00216 (33/15306). AF 95% confidence interval is 0.00158. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.15C>T	p.Ser5Ser	synonymous	Exon 1 of 3	NP_003914.1	O75593

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXH1	ENST00000377317.5	TSL:1 MANE Select	c.15C>T	p.Ser5Ser	synonymous	Exon 1 of 3	ENSP00000366534.4	O75593
FOXH1	ENST00000935088.1		c.15C>T	p.Ser5Ser	synonymous	Exon 1 of 3	ENSP00000605147.1
FOXH1	ENST00000935090.1		c.15C>T	p.Ser5Ser	synonymous	Exon 1 of 3	ENSP00000605149.1

Frequencies

GnomAD3 genomes

AF:

0.000874

AC:

133

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.000814

AC:

AN:

62666

AF XY:

0.000702

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00160

Gnomad ASJ exome

AF:

0.000809

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000945

Gnomad NFE exome

AF:

0.00126

Gnomad OTH exome

AF:

0.00254

GnomAD4 exome

AF:

0.00102

AC:

1293

AN:

1261966

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

612

AN XY:

609244

show subpopulations

African (AFR)

AF:

0.000183

AC:

AN:

27378

American (AMR)

AF:

0.00176

AC:

AN:

13620

Ashkenazi Jewish (ASJ)

AF:

0.000781

AC:

AN:

17922

East Asian (EAS)

AF:

0.00

AC:

AN:

32634

South Asian (SAS)

AF:

0.000462

AC:

AN:

54100

European-Finnish (FIN)

AF:

0.000228

AC:

AN:

43800

Middle Eastern (MID)

AF:

0.00141

AC:

AN:

4958

European-Non Finnish (NFE)

AF:

0.00115

AC:

1168

AN:

1015968

Other (OTH)

AF:

0.000775

AC:

AN:

51586

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

117

175

234

292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

138

184

230

<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:

0.000873

AC:

133

AN:

152274

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41556

American (AMR)

AF:

0.00216

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

67996

Other (OTH)

AF:

0.00285

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.000831

Hom.:

Bravo

AF:

0.00103

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Holoprosencephaly sequence (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

8.3

(source)

DANN

Benign

0.85

PhyloP100

-0.86

PromoterAI

-0.0022

Neutral

(source)

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

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

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