3-133811136-T-C

Variant names:

• chr3-133811136-T-C
• rs1935255261
• NM_001379313.1:c.347T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001379313.1(SRPRB):​c.347T>C​(p.Ile116Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SRPRB NM_001379313.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.55

Genes affected

SRPRB (HGNC:24085): (SRP receptor subunit beta) The protein encoded by this gene has similarity to mouse protein which is a subunit of the signal recognition particle receptor (SR). This subunit is a transmembrane GTPase belonging to the GTPase superfamily. It anchors alpha subunit, a peripheral membrane GTPase, to the ER membrane. SR is required for the cotranslational targeting of both secretory and membrane proteins to the ER membrane. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRPRB	NM_001379313.1	c.347T>C	p.Ile116Thr	missense_variant	Exon 4 of 7	ENST00000678299.1	NP_001366242.1
SRPRB	NM_021203.4	c.347T>C	p.Ile116Thr	missense_variant	Exon 5 of 8		NP_067026.3
SRPRB	NR_163491.1	n.381T>C		non_coding_transcript_exon_variant	Exon 4 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRPRB	ENST00000678299.1	c.347T>C	p.Ile116Thr	missense_variant	Exon 4 of 7		NM_001379313.1	ENSP00000503923.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461856 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.347T>C (p.I116T) alteration is located in exon 5 (coding exon 4) of the SRPRB gene. This alteration results from a T to C substitution at nucleotide position 347, causing the isoleucine (I) at amino acid position 116 to be replaced by a threonine (T). 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	0.30
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.84
MutPred		0.83		Loss of stability (P = 5e-04);
MVP		0.62
MPC		0.34
ClinPred		0.94	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1935255261; hg19: chr3-133529980;