rs151147114

Variant names:

• chr8-144474553-A-G
• rs151147114
• NM_003923.3:c.783T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003923.3(FOXH1):​c.783T>C​(p.Pro261Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,610,902 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (20 hom.)
• Consequence: FOXH1 NM_003923.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.77
• Publications: 0 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=-0.88).
• BP6: Variant 8-144474553-A-G is Benign according to our data. Variant chr8-144474553-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00272 (414/152296) while in subpopulation NFE AF = 0.00187 (127/67996). AF 95% confidence interval is 0.0016. There are 2 homozygotes in GnomAd4. There are 281 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXH1	NM_003923.3	MANE Select	c.783T>C	p.Pro261Pro	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.783T>C	p.Pro261Pro	synonymous	Exon 3 of 3	ENSP00000366534.4
	FOXH1	ENST00000935088.1		c.774T>C	p.Pro258Pro	synonymous	Exon 3 of 3	ENSP00000605147.1
	FOXH1	ENST00000935090.1		c.771T>C	p.Pro257Pro	synonymous	Exon 3 of 3	ENSP00000605149.1

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 414 AN: 152178 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0249

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00334 AC: 822 AN: 245768 AF XY: 0.00347

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000755

Gnomad ASJ exome AF: 0.000407

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0217

Gnomad NFE exome AF: 0.00279

Gnomad OTH exome AF: 0.00349

GnomAD4 exome AF: 0.00218 AC: 3181 AN: 1458606 Hom.: 20 Cov.: 35 AF XY: 0.00213 AC XY: 1548 AN XY: 725570

African (AFR) AF: 0.000150 AC: 5 AN: 33416

American (AMR) AF: 0.000761 AC: 34 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.0226 AC: 1173 AN: 52002

Middle Eastern (MID) AF: 0.000225 AC: 1 AN: 4438

European-Non Finnish (NFE) AF: 0.00164 AC: 1827 AN: 1111880

Other (OTH) AF: 0.00226 AC: 136 AN: 60210

GnomAD4 genome AF: 0.00272 AC: 414 AN: 152296 Hom.: 2 Cov.: 33 AF XY: 0.00377 AC XY: 281 AN XY: 74484

African (AFR) AF: 0.000337 AC: 14 AN: 41580

American (AMR) AF: 0.000392 AC: 6 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0249 AC: 264 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00187 AC: 127 AN: 67996

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00185 Hom.: 0

Bravo AF: 0.000903

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00190

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.17
DANN	Benign	0.39
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs151147114; hg19: chr8-145699936;