2-169811186-G-T

Position:

• chr2-169811186-G-T

Variant summary

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

The NM_003142.5(SSB):​c.1001G>T​(p.Arg334Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SSB NM_003142.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.97

Genes affected

SSB (HGNC:11316): (small RNA binding exonuclease protection factor La) The protein encoded by this gene is involved in diverse aspects of RNA metabolism, including binding and protecting poly(U) termini of nascent RNA polymerase III transcripts from exonuclease digestion, processing 5' and 3' ends of pre-tRNA precursors, acting as an RNA chaperone, and binding viral RNAs associated with hepatitis C virus. Autoantibodies reacting with this protein are found in the sera of patients with Sjogren syndrome and systemic lupus erythematosus. Alternative promoter usage results in two different transcript variants which encode the same protein. [provided by RefSeq, Jun 2014]

METTL5 (HGNC:25006): (methyltransferase 5, N6-adenosine) Enables S-adenosyl-L-methionine binding activity and rRNA (adenine-N6-)-methyltransferase activity. Involved in positive regulation of translation and rRNA methylation. Located in nucleus; postsynapse; and presynapse. Implicated in autosomal recessive intellectual developmental disorder-72. [provided by Alliance of Genome Resources, Apr 2022]

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/exons	MANE	Protein	UniProt
SSB	NM_003142.5	c.1001G>T	p.Arg334Leu	missense_variant	11/12	ENST00000260956.9	NP_003133.1
SSB	NM_001294145.2	c.1001G>T	p.Arg334Leu	missense_variant	11/12		NP_001281074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SSB	ENST00000260956.9	c.1001G>T	p.Arg334Leu	missense_variant	11/12	1	NM_003142.5	ENSP00000260956.4
SSB	ENST00000409333.1	c.1001G>T	p.Arg334Leu	missense_variant	11/12	1		ENSP00000386636.1
METTL5	ENST00000409837.5	c.592-842C>A		intron_variant		1		ENSP00000386703.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Oct 12, 2024

The c.1001G>T (p.R334L) alteration is located in exon 11 (coding exon 10) of the SSB gene. This alteration results from a G to T substitution at nucleotide position 1001, causing the arginine (R) at amino acid position 334 to be replaced by a leucine (L). 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	Uncertain	0.53
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;D
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	.;T
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.0	M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.18
Sift	Benign	0.094	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.014	B;B
Vest4		0.55
MutPred		0.62		Loss of helix (P = 0.0123);Loss of helix (P = 0.0123);
MVP		0.50
MPC		0.40
ClinPred		0.76	D
GERP RS		4.6
Varity_R		0.23
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-170667696;