14-34999643-A-G

Position:

• chr14-34999643-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003136.4(SRP54):​c.164A>G​(p.Asn55Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,578 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SRP54 NM_003136.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.14

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]

SRP54 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SRP54. . Gene score misZ 3.4521 (greater than the threshold 3.09). Trascript score misZ 3.7472 (greater than threshold 3.09). GenCC has associacion of gene with Shwachman-Diamond syndrome, neutropenia, severe congenital, 8, autosomal dominant, autosomal dominant severe congenital neutropenia.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRP54	NM_003136.4	c.164A>G	p.Asn55Ser	missense_variant	3/16	ENST00000216774.11	NP_003127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRP54	ENST00000216774.11	c.164A>G	p.Asn55Ser	missense_variant	3/16	1	NM_003136.4	ENSP00000216774.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456578 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2 AN XY: 724972

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Labcorp Genetics (formerly Invitae), Labcorp

Jul 29, 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. This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 55 of the SRP54 protein (p.Asn55Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SRP54-related conditions. ClinVar contains an entry for this variant (Variation ID: 2014872). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SRP54 protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;T;T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Benign	0.0074	T
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L;.;L
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Benign	0.15
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.14	B;.;B
Vest4		0.61
MutPred		0.40		Gain of phosphorylation at N55 (P = 0.0378);Gain of phosphorylation at N55 (P = 0.0378);Gain of phosphorylation at N55 (P = 0.0378);
MVP		0.48
MPC		0.82
ClinPred		0.73	D
GERP RS		5.6
Varity_R		0.35
gMVP		0.80

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: rs1264306584; hg19: chr14-35468849;