NM_012437.6:c.163C>T

Variant names:

• chr1-153659157-C-T
• rs1060499751
• NM_012437.6:c.163C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_012437.6(SNAPIN):​c.163C>T​(p.Arg55Trp) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNAPIN NM_012437.6 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.95
• Publications: 0 publications found

Genes affected

SNAPIN (HGNC:17145): (SNAP associated protein) The protein encoded by this gene is a coiled-coil-forming protein that associates with the SNARE (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor) complex of proteins and the BLOC-1 (biogenesis of lysosome-related organelles) complex. Biochemical studies have identified additional binding partners. As part of the SNARE complex, it is required for vesicle docking and fusion and regulates neurotransmitter release. The BLOC-1 complex is required for the biogenesis of specialized organelles such as melanosomes and platelet dense granules. Mutations in gene products that form the BLOC-1 complex have been identified in mouse strains that are models of Hermansky-Pudlak syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

ACMG classification

Our verdict: Pathogenic. The variant received 13 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 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.87794 (below the threshold of 3.09). Trascript score misZ: -0.074464 (below the threshold of 3.09).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856
• PP5: Variant 1-153659157-C-T is Pathogenic according to our data. Variant chr1-153659157-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 402168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012437.6. 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
	SNAPIN	NM_012437.6	MANE Select	c.163C>T	p.Arg55Trp	missense	Exon 2 of 4	NP_036569.1
	SNAPIN	NR_052019.1		n.233+271C>T		intron	N/A
	SNAPIN	NR_052020.1		n.219+285C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNAPIN	ENST00000368685.6	TSL:1 MANE Select	c.163C>T	p.Arg55Trp	missense	Exon 2 of 4	ENSP00000357674.5
	SNAPIN	ENST00000971969.1		c.163C>T	p.Arg55Trp	missense	Exon 2 of 4	ENSP00000642028.1
	SNAPIN	ENST00000911963.1		c.163C>T	p.Arg55Trp	missense	Exon 2 of 5	ENSP00000582022.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Abnormal brain morphology (1)
1	-	-	NEURODEVELOPMENTAL DISORDER WITH STRUCTURAL BRAIN ABNORMALITIES AND CRANIOFACIAL ABNORMALITIES (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.35		Loss of disorder (P = 0.0087)
MVP		0.72
MPC		0.70
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		-0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.73
Mutation Taster		=32/68	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: -19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1060499751; hg19: chr1-153631633;