NM_032410.4:c.225T>G

Variant names:

• chr8-42930130-T-G
• rs1563293555
• NM_032410.4:c.225T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_032410.4(HOOK3):​c.225T>G​(p.Asn75Lys) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HOOK3 NM_032410.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.783
• 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: Likely_pathogenic. The variant received 8 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, 0.974
• PP5: Variant 8-42930130-T-G is Pathogenic according to our data. Variant chr8-42930130-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 599519.Status of the report is no_assertion_criteria_provided, 0 stars.

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.225T>G	p.Asn75Lys	missense	Exon 4 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.225T>G	p.Asn75Lys	missense	Exon 4 of 22	ENSP00000305699.3	Q86VS8
	HOOK3	ENST00000527306.1	TSL:1	n.411T>G		non_coding_transcript_exon	Exon 4 of 16
	HOOK3	ENST00000862681.1		c.225T>G	p.Asn75Lys	missense	Exon 4 of 23	ENSP00000532740.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Short stature (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.78
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.36
Sift	Benign	0.083	T
Sift4G	Benign	0.079	T
Polyphen		1.0	D
Vest4		0.84
MutPred		0.94		Gain of MoRF binding (P = 0.0531)
MVP		0.75
MPC		1.4
ClinPred		0.99	D
GERP RS		0.29
Varity_R		0.89
gMVP		0.79
Mutation Taster		=31/69	disease causing (ClinVar)

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: rs1563293555; hg19: chr8-42785273;