22-24567986-G-A

Variant names:

• chr22-24567986-G-A
• rs2045212242
• NM_004175.5:c.129G>A

Variant summary

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

The NM_004175.5(SNRPD3):​c.129G>A​(p.Met43Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNRPD3 NM_004175.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

SNRPD3 (HGNC:11160): (small nuclear ribonucleoprotein D3 polypeptide) This gene encodes a core component of the spliceosome, which is a nuclear ribonucleoprotein complex that functions in pre-mRNA splicing. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ENSG00000286070 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNRPD3	NM_004175.5	c.129G>A	p.Met43Ile	missense_variant, splice_region_variant	Exon 3 of 4	ENST00000215829.8	NP_004166.1
SNRPD3	NM_001278656.2	c.129G>A	p.Met43Ile	missense_variant, splice_region_variant	Exon 3 of 4		NP_001265585.1
SNRPD3	NR_103819.1	n.567-3930G>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNRPD3	ENST00000215829.8	c.129G>A	p.Met43Ile	missense_variant, splice_region_variant	Exon 3 of 4	1	NM_004175.5	ENSP00000215829.3
ENSG00000286070	ENST00000652248.1	n.129G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 20			ENSP00000499210.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.129G>A (p.M43I) alteration is located in exon 3 (coding exon 2) of the SNRPD3 gene. This alteration results from a G to A substitution at nucleotide position 129, causing the methionine (M) at amino acid position 43 to be replaced by an isoleucine (I). 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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Benign	0.0076	T
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.23
Sift	Benign	0.047	D;D
Sift4G	Benign	0.091	T;T
Polyphen		0.022	B;.
Vest4		0.70
MutPred		0.67		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.83
MPC		1.7
ClinPred		0.81	D
GERP RS		5.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.66
gMVP		0.89

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: rs2045212242; hg19: chr22-24963954;