rs374587860

Variant names:

• chr8-144475742-G-A
• rs374587860
• NM_003923.3:c.15C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.860

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 215825.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 133 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXH1	NM_003923.3	c.15C>T	p.Ser5Ser	synonymous_variant	Exon 1 of 3	ENST00000377317.5	NP_003914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXH1	ENST00000377317.5	c.15C>T	p.Ser5Ser	synonymous_variant	Exon 1 of 3	1	NM_003923.3	ENSP00000366534.4
FOXH1	ENST00000525197.1	n.82C>T		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152156 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000814 AC: 51 AN: 62666 Hom.: 0 AF XY: 0.000702 AC XY: 22 AN XY: 31344

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 SAS exome AF: 0.000447

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.: 0 Cov.: 32 AF XY: 0.00100 AC XY: 612 AN XY: 609244

Gnomad4 AFR exome AF: 0.000183

Gnomad4 AMR exome AF: 0.00176

Gnomad4 ASJ exome AF: 0.000781

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000462

Gnomad4 FIN exome AF: 0.000228

Gnomad4 NFE exome AF: 0.00115

Gnomad4 OTH exome AF: 0.000775

GnomAD4 genome AF: 0.000873 AC: 133 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.000765 AC XY: 57 AN XY: 74464

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.000831 Hom.: 0

Bravo AF: 0.00103

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Holoprosencephaly sequence Benign:2

Jun 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Uncertain:1

Jun 26, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	8.3
DANN	Benign	0.85

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

LitVar

Other links and lift over

dbSNP: rs374587860; hg19: chr8-145701125; COSMIC: COSV56760377; COSMIC: COSV56760377;