NM_005701.4:c.553G>A

Variant names:

• chr15-75607263-C-T
• rs148518590
• NM_005701.4:c.553G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005701.4(SNUPN):​c.553G>A​(p.Val185Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,613,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: SNUPN NM_005701.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.122193605).

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.553G>A	p.Val185Ile	missense	Exon 6 of 9	NP_005692.1	O95149
	SNUPN	NM_001042581.2		c.553G>A	p.Val185Ile	missense	Exon 6 of 9	NP_001036046.1	O95149
	SNUPN	NM_001042588.2		c.553G>A	p.Val185Ile	missense	Exon 6 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.553G>A	p.Val185Ile	missense	Exon 6 of 9	ENSP00000309831.5	O95149
	SNUPN	ENST00000896168.1		c.553G>A	p.Val185Ile	missense	Exon 6 of 9	ENSP00000566227.1
	SNUPN	ENST00000934023.1		c.553G>A	p.Val185Ile	missense	Exon 6 of 9	ENSP00000604082.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000155 AC: 39 AN: 251184 AF XY: 0.000184

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000157 AC: 230 AN: 1461574 Hom.: 0 Cov.: 30 AF XY: 0.000150 AC XY: 109 AN XY: 727090

African (AFR) AF: 0.0000598 AC: 2 AN: 33470

American (AMR) AF: 0.0000671 AC: 3 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000184 AC: 205 AN: 1111756

Other (OTH) AF: 0.000133 AC: 8 AN: 60376

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74322

African (AFR) AF: 0.0000483 AC: 2 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000190 Hom.: 0

Bravo AF: 0.000162

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000327

EpiControl AF: 0.00

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	Benign	0.070
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.060
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.56	N
PhyloP100		1.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.053
Sift	Benign	0.42	T
Sift4G	Benign	0.74	T
Polyphen		0.0020	B
Vest4		0.32
MVP		0.25
MPC		0.10
ClinPred		0.11	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.044
gMVP		0.18
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148518590; hg19: chr15-75899604;