17-76043849-C-T

Variant names:

• chr17-76043849-C-T
• rs150844153
• NM_014230.4:c.1504G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014230.4(SRP68):​c.1504G>A​(p.Ala502Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000283 in 1,603,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: SRP68 NM_014230.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48

Genes affected

SRP68 (HGNC:11302): (signal recognition particle 68) This gene encodes a subunit of the signal recognition particle (SRP). The SRP is a ribonucleoprotein complex that transports secreted and membrane proteins to the endoplasmic reticulum for processing. The complex includes a 7S RNA and six protein subunits. The encoded protein is the 68kDa component of the SRP, and forms a heterodimer with the 72kDa subunit that is required for SRP function. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and three pseudogenes of this gene are located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05671093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRP68	NM_014230.4	c.1504G>A	p.Ala502Thr	missense_variant	Exon 13 of 16	ENST00000307877.7	NP_055045.2
SRP68	NM_001260502.2	c.1390G>A	p.Ala464Thr	missense_variant	Exon 12 of 15		NP_001247431.1
SRP68	NM_001260503.2	c.487G>A	p.Ala163Thr	missense_variant	Exon 6 of 9		NP_001247432.1
SRP68	NR_048541.2	n.1426G>A		non_coding_transcript_exon_variant	Exon 12 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRP68	ENST00000307877.7	c.1504G>A	p.Ala502Thr	missense_variant	Exon 13 of 16	1	NM_014230.4	ENSP00000312066.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000184 AC: 44 AN: 239610 Hom.: 0 AF XY: 0.000193 AC XY: 25 AN XY: 129690

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000649

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000712

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00120

GnomAD4 exome AF: 0.000288 AC: 418 AN: 1451048 Hom.: 0 Cov.: 32 AF XY: 0.000292 AC XY: 211 AN XY: 721790

Gnomad4 AFR exome AF: 0.0000919

Gnomad4 AMR exome AF: 0.000121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000238

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000350

Gnomad4 OTH exome AF: 0.000300

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74330

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000293 Hom.: 0

Bravo AF: 0.000181

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000165 AC: 20

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000238

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1504G>A (p.A502T) alteration is located in exon 13 (coding exon 13) of the SRP68 gene. This alteration results from a G to A substitution at nucleotide position 1504, causing the alanine (A) at amino acid position 502 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	0.062
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.016	.;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.057	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	.;L;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.69	.;N;N
REVEL	Benign	0.046
Sift	Benign	0.35	.;T;T
Sift4G	Benign	0.59	T;T;T
Polyphen		0.043	.;B;.
Vest4		0.073
MVP		0.77
MPC		0.53
ClinPred		0.038	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.11

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: rs150844153; hg19: chr17-74039930;