17-76040939-A-C

Variant names:

• chr17-76040939-A-C
• NM_014230.4:c.1564T>G

Variant summary

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

The NM_014230.4(SRP68):​c.1564T>G​(p.Ser522Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRP68 NM_014230.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.06

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 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=0.10507694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRP68	NM_014230.4	c.1564T>G	p.Ser522Ala	missense_variant	Exon 14 of 16	ENST00000307877.7	NP_055045.2
SRP68	NM_001260502.2	c.1450T>G	p.Ser484Ala	missense_variant	Exon 13 of 15		NP_001247431.1
SRP68	NM_001260503.2	c.547T>G	p.Ser183Ala	missense_variant	Exon 7 of 9		NP_001247432.1
SRP68	NR_048541.2	n.1486T>G		non_coding_transcript_exon_variant	Exon 13 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRP68	ENST00000307877.7	c.1564T>G	p.Ser522Ala	missense_variant	Exon 14 of 16	1	NM_014230.4	ENSP00000312066.1

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

Sep 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1564T>G (p.S522A) alteration is located in exon 14 (coding exon 14) of the SRP68 gene. This alteration results from a T to G substitution at nucleotide position 1564, causing the serine (S) at amino acid position 522 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	0.050
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Benign	0.50
DEOGEN2	Benign	0.013	.;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.087
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.00056	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.99	.;N;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.24	.;N;N
REVEL	Benign	0.25
Sift	Benign	1.0	.;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.16
MutPred		0.29		.;Gain of helix (P = 0.0078);.;
MVP		0.35
MPC		0.45
ClinPred		0.63	D
GERP RS		4.9
Varity_R		0.066
gMVP		0.14

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: chr17-74037020;