rs1004380299

Variant names:

• chr15-75617547-C-A
• rs1004380299
• NM_005701.4:c.164G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-75617547-C-A
• chr15-75617547-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_005701.4(SNUPN):​c.164G>T​(p.Arg55Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R55Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SNUPN NM_005701.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.10
• Publications: 0 publications found

Genes affected

SNUPN (HGNC:14245): (snurportin 1) The nuclear import of the spliceosomal snRNPs U1, U2, U4 and U5, is dependent on the presence of a complex nuclear localization signal. The latter is composed of the 5'-2,2,7-terminal trimethylguanosine (m3G) cap structure of the U snRNA and the Sm core domain. The protein encoded by this gene interacts specifically with m3G-cap and functions as an snRNP-specific nuclear import receptor. Alternatively spliced transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

SNUPN Gene-Disease associations (from GenCC):

• muscular dystrophy, limb-girdle, autosomal recessive 29

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Ambry Genetics
• SNUPN-related muscular dystrophy with or without multi-system involvement

  Inheritance: AR Classification: STRONG Submitted by: ClinGen

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-75617547-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2466334.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005701.4. 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
	SNUPN	NM_005701.4	MANE Select	c.164G>T	p.Arg55Leu	missense	Exon 3 of 9	NP_005692.1	O95149
	SNUPN	NM_001042581.2		c.164G>T	p.Arg55Leu	missense	Exon 3 of 9	NP_001036046.1	O95149
	SNUPN	NM_001042588.2		c.164G>T	p.Arg55Leu	missense	Exon 3 of 9	NP_001036053.1	O95149

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNUPN	ENST00000308588.10	TSL:1 MANE Select	c.164G>T	p.Arg55Leu	missense	Exon 3 of 9	ENSP00000309831.5	O95149
	SNUPN	ENST00000896168.1		c.164G>T	p.Arg55Leu	missense	Exon 3 of 9	ENSP00000566227.1
	SNUPN	ENST00000934023.1		c.164G>T	p.Arg55Leu	missense	Exon 3 of 9	ENSP00000604082.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453752 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723196

African (AFR) AF: 0.00 AC: 0 AN: 32818

American (AMR) AF: 0.00 AC: 0 AN: 42268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 84252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109866

Other (OTH) AF: 0.00 AC: 0 AN: 60008

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.36
Sift	Benign	0.062	T
Sift4G	Benign	0.076	T
Polyphen		1.0	D
Vest4		0.90
MVP		0.59
MPC		0.64
ClinPred		1.0	D
GERP RS		2.7
PromoterAI		-0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.81
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 1

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

Other links and lift over

dbSNP: rs1004380299; hg19: chr15-75909888;