8-42959307-A-T

Variant names:

• chr8-42959307-A-T
• NM_032410.4:c.608A>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_032410.4(HOOK3):​c.608A>T​(p.Asp203Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: HOOK3 NM_032410.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.88
• Publications: 0 publications found

Genes affected

HOOK3 (HGNC:23576): (hook microtubule tethering protein 3) Hook proteins are cytosolic coiled-coil proteins that contain conserved N-terminal domains, which attach to microtubules, and more divergent C-terminal domains, which mediate binding to organelles. The Drosophila Hook protein is a component of the endocytic compartment.[supplied by OMIM, Apr 2004]

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.3553 (below the threshold of 3.09). Trascript score misZ: 1.6655 (below the threshold of 3.09).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032410.4. 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
	HOOK3	NM_032410.4	MANE Select	c.608A>T	p.Asp203Val	missense	Exon 8 of 22	NP_115786.1	Q86VS8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOOK3	ENST00000307602.9	TSL:1 MANE Select	c.608A>T	p.Asp203Val	missense	Exon 8 of 22	ENSP00000305699.3	Q86VS8
	HOOK3	ENST00000527306.1	TSL:1	n.794A>T		non_coding_transcript_exon	Exon 8 of 16
	HOOK3	ENST00000862681.1		c.644A>T	p.Asp215Val	missense	Exon 9 of 23	ENSP00000532740.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.55		Loss of disorder (P = 0.087)
MVP		0.70
MPC		1.5
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.85
gMVP		0.60
Mutation Taster		=32/68	disease causing

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

hg19: chr8-42814450;