rs80356380

Variant names:

• chr8-144474973-C-G
• rs80356380
• NM_003923.3:c.363G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-144474973-C-G
• chr8-144474973-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003923.3(FOXH1):​c.363G>C​(p.Arg121Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00629 in 1,607,518 control chromosomes in the GnomAD database, including 526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R121R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.034 (287 hom., cov: 34)
  • Exomes 𝑓: 0.0034 (239 hom.)
• Consequence: FOXH1 NM_003923.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0860
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• congenital heart malformation

  Inheritance: Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 8-144474973-C-G is Benign according to our data. Variant chr8-144474973-C-G is described in ClinVar as Benign. ClinVar VariationId is 137394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.086 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXH1	NM_003923.3	MANE Select	c.363G>C	p.Arg121Arg	synonymous	Exon 3 of 3	NP_003914.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXH1	ENST00000377317.5	TSL:1 MANE Select	c.363G>C	p.Arg121Arg	synonymous	Exon 3 of 3	ENSP00000366534.4
	FOXH1	ENST00000935088.1		c.354G>C	p.Arg118Arg	synonymous	Exon 3 of 3	ENSP00000605147.1
	FOXH1	ENST00000935090.1		c.351G>C	p.Arg117Arg	synonymous	Exon 3 of 3	ENSP00000605149.1

Frequencies

GnomAD3 genomes AF: 0.0340 AC: 5181 AN: 152208 Hom.: 286 Cov.: 34

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0224

GnomAD2 exomes AF: 0.00816 AC: 1882 AN: 230642 AF XY: 0.00615

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.00591

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000235

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.00339 AC: 4927 AN: 1455192 Hom.: 239 Cov.: 35 AF XY: 0.00290 AC XY: 2097 AN XY: 723600

African (AFR) AF: 0.118 AC: 3937 AN: 33332

American (AMR) AF: 0.00663 AC: 293 AN: 44180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39466

South Asian (SAS) AF: 0.000175 AC: 15 AN: 85498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50700

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5750

European-Non Finnish (NFE) AF: 0.000190 AC: 211 AN: 1110198

Other (OTH) AF: 0.00757 AC: 455 AN: 60096

GnomAD4 genome AF: 0.0340 AC: 5184 AN: 152326 Hom.: 287 Cov.: 34 AF XY: 0.0332 AC XY: 2475 AN XY: 74476

African (AFR) AF: 0.119 AC: 4962 AN: 41566

American (AMR) AF: 0.0104 AC: 159 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68026

Other (OTH) AF: 0.0222 AC: 47 AN: 2116

Alfa AF: 0.0103 Hom.: 28

Bravo AF: 0.0385

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Holoprosencephaly sequence (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.7
DANN	Benign	0.68
PhyloP100		0.086
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80356380; hg19: chr8-145700356; COSMIC: COSV56762631; COSMIC: COSV56762631;