8-144474272-C-T

Variant names:

• chr8-144474272-C-T
• rs1289939767
• NM_003923.3:c.1064G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003923.3(FOXH1):​c.1064G>A​(p.Gly355Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000439 in 1,595,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: FOXH1 NM_003923.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.976
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14314991).

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.1064G>A	p.Gly355Asp	missense	Exon 3 of 3	NP_003914.1	O75593
	KIFC2	NM_001369769.2	MANE Select	c.*883C>T		downstream_gene	N/A	NP_001356698.1	A0A2R8YEU8
	KIFC2	NM_145754.5		c.*822C>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.1064G>A	p.Gly355Asp	missense	Exon 3 of 3	ENSP00000366534.4	O75593
	FOXH1	ENST00000935088.1		c.1055G>A	p.Gly352Asp	missense	Exon 3 of 3	ENSP00000605147.1
	FOXH1	ENST00000935090.1		c.1052G>A	p.Gly351Asp	missense	Exon 3 of 3	ENSP00000605149.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000427 AC: 1 AN: 234418 AF XY: 0.00

Gnomad AFR exome AF: 0.0000660

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000416 AC: 6 AN: 1443360 Hom.: 0 Cov.: 35 AF XY: 0.00000698 AC XY: 5 AN XY: 716044

African (AFR) AF: 0.00 AC: 0 AN: 33092

American (AMR) AF: 0.00 AC: 0 AN: 43598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24636

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 83742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00000544 AC: 6 AN: 1102096

Other (OTH) AF: 0.00 AC: 0 AN: 59542

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000370 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	8.6
DANN	Benign	0.91
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.98
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.26
Sift	Benign	0.11	T
Sift4G	Benign	0.25	T
Polyphen		0.010	B
Vest4		0.19
MVP		0.81
MPC		0.032
ClinPred		0.084	T
GERP RS		2.5
Varity_R		0.093
gMVP		0.42
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs1289939767; hg19: chr8-145699655;