8-144474352-G-T

Variant names:

• chr8-144474352-G-T
• rs117754060
• NM_003923.3:c.984C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003923.3(FOXH1):​c.984C>A​(p.Asp328Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in Lovd.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FOXH1 NM_003923.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.351

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXH1	NM_003923.3	c.984C>A	p.Asp328Glu	missense_variant	Exon 3 of 3	ENST00000377317.5	NP_003914.1
KIFC2	NM_001369769.2	c.*963G>T		downstream_gene_variant		ENST00000645548.2	NP_001356698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXH1	ENST00000377317.5	c.984C>A	p.Asp328Glu	missense_variant	Exon 3 of 3	1	NM_003923.3	ENSP00000366534.4
KIFC2	ENST00000645548.2	c.*963G>T		downstream_gene_variant			NM_001369769.2	ENSP00000494595.1
KIFC2	ENST00000301332.3	c.*902G>T		downstream_gene_variant		1		ENSP00000301332.2
KIFC2	ENST00000643461.1	n.*150G>T		downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	1.9
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.1	M
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.91	N
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.96	D
Vest4		0.23
MutPred		0.74		Gain of solvent accessibility (P = 0.3089);
MVP		0.91
MPC		0.21
ClinPred		0.94	D
GERP RS		-2.3
Varity_R		0.71
gMVP		0.67

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: rs117754060; hg19: chr8-145699735;