17-76043906-G-C

Variant names:

• chr17-76043906-G-C
• NM_014230.4:c.1447C>G

Variant summary

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

The NM_014230.4(SRP68):​c.1447C>G​(p.Leu483Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 4.58

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 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
SRP68	NM_014230.4	c.1447C>G	p.Leu483Val	missense_variant	Exon 13 of 16	ENST00000307877.7	NP_055045.2
SRP68	NM_001260502.2	c.1333C>G	p.Leu445Val	missense_variant	Exon 12 of 15		NP_001247431.1
SRP68	NM_001260503.2	c.430C>G	p.Leu144Val	missense_variant	Exon 6 of 9		NP_001247432.1
SRP68	NR_048541.2	n.1369C>G		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.1447C>G	p.Leu483Val	missense_variant	Exon 13 of 16	1	NM_014230.4	ENSP00000312066.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1447C>G (p.L483V) alteration is located in exon 13 (coding exon 13) of the SRP68 gene. This alteration results from a C to G substitution at nucleotide position 1447, causing the leucine (L) at amino acid position 483 to be replaced by a valine (V). 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	0.15
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.023	.;T;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;L;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.18	.;N;N
REVEL	Benign	0.17
Sift	Benign	0.67	.;T;T
Sift4G	Benign	0.70	T;T;T
Polyphen		0.42	.;B;.
Vest4		0.76
MutPred		0.54		.;Loss of loop (P = 0.0235);.;
MVP		0.48
MPC		0.89
ClinPred		0.69	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.41

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: chr17-74039987;