rs2721176

Positions:

• chr8-144474218-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003923.3(FOXH1):​c.*20A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.989 in 1,519,038 control chromosomes in the GnomAD database, including 744,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (73859 hom., cov: 34)
  • Exomes 𝑓: 0.99 (670576 hom.)
• Consequence: FOXH1 NM_003923.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.17

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]

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-144474218-T-C is Benign according to our data. Variant chr8-144474218-T-C is described in ClinVar as [Benign]. Clinvar id is 259199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144474218-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXH1	NM_003923.3	c.*20A>G		3_prime_UTR_variant	3/3	ENST00000377317.5	NP_003914.1
KIFC2	NM_001369769.2	c.*829T>C		downstream_gene_variant		ENST00000645548.2	NP_001356698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXH1	ENST00000377317.5	c.*20A>G		3_prime_UTR_variant	3/3	1	NM_003923.3	ENSP00000366534.4
KIFC2	ENST00000645548.2	c.*829T>C		downstream_gene_variant			NM_001369769.2	ENSP00000494595.1
KIFC2	ENST00000643461.1	n.*16T>C		downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.984 AC: 149776 AN: 152196 Hom.: 73806 Cov.: 34

Gnomad AFR AF: 0.986

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.951

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.997

Gnomad FIN AF: 0.998

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.989

GnomAD3 exomes AF: 0.965 AC: 165617 AN: 171596 Hom.: 80293 AF XY: 0.971 AC XY: 90084 AN XY: 92782

Gnomad AFR exome AF: 0.987

Gnomad AMR exome AF: 0.897

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 0.791

Gnomad SAS exome AF: 0.998

Gnomad FIN exome AF: 0.997

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.980

GnomAD4 exome AF: 0.990 AC: 1352452 AN: 1366724 Hom.: 670576 Cov.: 26 AF XY: 0.990 AC XY: 664836 AN XY: 671466

Gnomad4 AFR exome AF: 0.986

Gnomad4 AMR exome AF: 0.907

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 0.753

Gnomad4 SAS exome AF: 0.998

Gnomad4 FIN exome AF: 0.996

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.988

GnomAD4 genome AF: 0.984 AC: 149888 AN: 152314 Hom.: 73859 Cov.: 34 AF XY: 0.982 AC XY: 73156 AN XY: 74472

Gnomad4 AFR AF: 0.986

Gnomad4 AMR AF: 0.951

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 0.803

Gnomad4 SAS AF: 0.997

Gnomad4 FIN AF: 0.998

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.988

Alfa AF: 0.994 Hom.: 15845

Bravo AF: 0.978

Asia WGS AF: 0.943 AC: 3280 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Holoprosencephaly sequence Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.0
DANN	Benign	0.35

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: rs2721176; hg19: chr8-145699601; COSMIC: COSV56762547; COSMIC: COSV56762547;