14-34996756-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PP2 PP3 BS2

The NM_003136.4(SRP54):c.47C>T(p.Ser16Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,612,892 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 (★). Synonymous variant affecting the same amino acid position (i.e. S16S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SRP54 NM_003136.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.52

Genes affected

SRP54 (HGNC:11301): (signal recognition particle 54) Enables several functions, including 7S RNA binding activity; endoplasmic reticulum signal peptide binding activity; and guanyl ribonucleotide binding activity. Contributes to GTPase activity. Involved in granulocyte differentiation and protein targeting to ER. Located in cytosol and nucleus. Part of signal recognition particle, endoplasmic reticulum targeting. Implicated in severe congenital neutropenia 8. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a region_of_interest NG domain (size 294) in uniprot entity SRP54_HUMAN there are 15 pathogenic changes around while only 3 benign (83%) in NM_003136.4
• PP2: Missense variant where missense usually causes diseases, SRP54
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8
• BS2: High AC in GnomAdExome at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRP54	NM_003136.4	c.47C>T	p.Ser16Leu	missense_variant	2/16	ENST00000216774.11
SRP54	NM_001411017.1	c.47C>T	p.Ser16Leu	missense_variant	2/15
SRP54	XM_011537106.1	c.47C>T	p.Ser16Leu	missense_variant	2/16
SRP54	NM_001146282.2	c.-9C>T		5_prime_UTR_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRP54	ENST00000216774.11	c.47C>T	p.Ser16Leu	missense_variant	2/16	1	NM_003136.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251358 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1460798 Hom.: 0 Cov.: 29 AF XY: 0.00000963 AC XY: 7 AN XY: 726778

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

Gnomad4 AFR AF: 0.00

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 03, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SRP54 protein function. This variant has not been reported in the literature in individuals affected with SRP54-related conditions. This variant is present in population databases (rs775147862, gnomAD 0.02%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 16 of the SRP54 protein (p.Ser16Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;T;T;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.0082	T
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	3.1	M;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	D;D;D;D;.
REVEL	Uncertain	0.61
Sift	Benign	0.061	T;T;T;T;.
Sift4G	Benign	0.12	T;D;D;T;D
Polyphen		1.0	D;.;.;D;.
Vest4		0.76
MutPred		0.50		Loss of disorder (P = 0.0674);Loss of disorder (P = 0.0674);Loss of disorder (P = 0.0674);Loss of disorder (P = 0.0674);Loss of disorder (P = 0.0674);
MVP		0.46
MPC		1.5
ClinPred		0.96	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.36
gMVP		0.69

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: rs775147862; hg19: chr14-35465962; COSMIC: COSV53741115;