8-144474217-G-T

Variant names:

• chr8-144474217-G-T
• rs1825066619
• NM_003923.3:c.*21C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003923.3(FOXH1):​c.*21C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXH1 NM_003923.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.63
• 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]

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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.*21C>A		3_prime_UTR	Exon 3 of 3	NP_003914.1	O75593
	KIFC2	NM_001369769.2	MANE Select	c.*828G>T		downstream_gene	N/A	NP_001356698.1	A0A2R8YEU8
	KIFC2	NM_145754.5		c.*767G>T		downstream_gene	N/A	NP_665697.1	Q96AC6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXH1	ENST00000377317.5	TSL:1 MANE Select	c.*21C>A		3_prime_UTR	Exon 3 of 3	ENSP00000366534.4	O75593
	FOXH1	ENST00000935088.1		c.*21C>A		3_prime_UTR	Exon 3 of 3	ENSP00000605147.1
	FOXH1	ENST00000935090.1		c.*21C>A		3_prime_UTR	Exon 3 of 3	ENSP00000605149.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1368090 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 672544

African (AFR) AF: 0.00 AC: 0 AN: 30642

American (AMR) AF: 0.00 AC: 0 AN: 32946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20826

East Asian (EAS) AF: 0.00 AC: 0 AN: 38798

South Asian (SAS) AF: 0.00 AC: 0 AN: 72644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5152

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1062262

Other (OTH) AF: 0.00 AC: 0 AN: 56280

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Holoprosencephaly sequence (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.0
DANN	Benign	0.53
PhyloP100		2.6

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

Other links and lift over

dbSNP: rs1825066619; hg19: chr8-145699600;