19-40759588-G-C

Position:

• chr19-40759588-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004596.5(SNRPA):​c.404G>C​(p.Gly135Ala) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SNRPA NM_004596.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.283

Genes affected

SNRPA (HGNC:11151): (small nuclear ribonucleoprotein polypeptide A) The protein encoded by this gene associates with stem loop II of the U1 small nuclear ribonucleoprotein, which binds the 5' splice site of precursor mRNAs and is required for splicing. The encoded protein autoregulates itself by polyadenylation inhibition of its own pre-mRNA via dimerization and has been implicated in the coupling of splicing and polyadenylation. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070353985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNRPA	NM_004596.5	c.404G>C	p.Gly135Ala	missense_variant	3/6	ENST00000243563.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNRPA	ENST00000243563.8	c.404G>C	p.Gly135Ala	missense_variant	3/6	1	NM_004596.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.404G>C (p.G135A) alteration is located in exon 3 (coding exon 3) of the SNRPA gene. This alteration results from a G to C substitution at nucleotide position 404, causing the glycine (G) at amino acid position 135 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	19
DANN	Benign	0.30
DEOGEN2	Benign	0.11	.;T;T;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.70	T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.070	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.27	.;N;.;.;.
MutationTaster	Benign	0.83	N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.59	.;N;.;.;.
REVEL	Benign	0.079
Sift	Benign	0.61	.;T;.;.;.
Sift4G	Benign	0.67	T;T;T;T;T
Polyphen		0.0	.;B;.;.;.
Vest4		0.17
MutPred		0.27		.;Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);.;
MVP		0.31
MPC		0.63
ClinPred		0.066	T
GERP RS		4.6
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.1
Varity_R		0.079
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs2082923055; hg19: chr19-41265493;