8-144474215-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.798

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]

ACMG classification

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 GnomAd at 37 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152232 Hom.: 0 Cov.: 32

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: 49 AN: 170022 Hom.: 0 AF XY: 0.000338 AC XY: 31 AN XY: 91844

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.: 0 Cov.: 25 AF XY: 0.000422 AC XY: 283 AN XY: 671254

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: 37 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74500

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.: 0

Bravo AF: 0.000351

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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

Other links and lift over

dbSNP: rs541830947; hg19: chr8-145699598;