chr8-144474215-G-A

Position:

chr8-144474215-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_003923.3(FOXH1):c.*23C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000414 in 1,517,744 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

FOXH1
NM_003923.3 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.798

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:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 8-144474215-G-A is Benign according to our data. Variant chr8-144474215-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 362277.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000243 (37/152350) while in subpopulation NFE AF= 0.000412 (28/68024). AF 95% confidence interval is 0.000292. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXH1	NM_003923.3 linkuse as main transcript	c.*23C>T		3_prime_UTR_variant	3/3	ENST00000377317.5
KIFC2	NM_001369769.2 linkuse as main transcript			downstream_gene_variant		ENST00000645548.2

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris
FOXH1	ENST00000377317.5 linkuse as main transcript	c.*23C>T	3_prime_UTR_variant	3/3	1	NM_003923.3	P1
KIFC2	ENST00000645548.2 linkuse as main transcript		downstream_gene_variant			NM_001369769.2	P1
KIFC2	ENST00000643461.1 linkuse as main transcript		downstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000288

AC:

AN:

170022

Hom.:

AF XY:

0.000338

AC XY:

AN XY:

91844

show subpopulations

Gnomad AFR exome

AF:

0.000159

Gnomad AMR exome

AF:

0.0000847

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000513

Gnomad OTH exome

AF:

0.00126

GnomAD4 exome

AF:

0.000433

AC:

591

AN:

1365394

Hom.:

Cov.:

AF XY:

0.000422

AC XY:

283

AN XY:

671254

show subpopulations

Gnomad4 AFR exome

AF:

0.000196

Gnomad4 AMR exome

AF:

0.0000610

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000165

Gnomad4 NFE exome

AF:

0.000524

Gnomad4 OTH exome

AF:

0.000338

GnomAD4 genome

AF:

0.000243

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000172

Hom.:

Bravo

AF:

0.000351

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Holoprosencephaly sequence

Benign:1

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.5

DANN

Benign

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over