rs1060499751

chr1-153659157-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

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, single submitter P:1
• Conservation: PhyloP100: 2.95

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 402168.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNAPIN	NM_012437.6	c.163C>T	p.Arg55Trp	missense_variant	2/4	ENST00000368685.6
SNAPIN	NR_052019.1	n.233+271C>T		intron_variant, non_coding_transcript_variant
SNAPIN	NR_052020.1	n.219+285C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNAPIN	ENST00000368685.6	c.163C>T	p.Arg55Trp	missense_variant	2/4	1	NM_012437.6	P1
SNAPIN	ENST00000474959.5	n.446C>T		non_coding_transcript_exon_variant	1/3	2
SNAPIN	ENST00000478558.1	n.431C>T		non_coding_transcript_exon_variant	1/2	2
SNAPIN	ENST00000462880.1	n.173+271C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

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Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060499751; hg19: chr1-153631633;