14-34999572-G-C

Position:

• chr14-34999572-G-C

Variant summary

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

The NM_003136.4(SRP54):​c.93G>C​(p.Met31Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,134 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SRP54 NM_003136.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.80

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.93G>C	p.Met31Ile	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.93G>C	p.Met31Ile	missense_variant	3/16	1	NM_003136.4	ENSP00000216774.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74306

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

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

GeneDx

Apr 17, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T;T;T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Benign	0.0071	T
MetaRNN	Uncertain	0.62	D;D;D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.1	M;.;.;M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.1	N;N;N;N;.
REVEL	Benign	0.28
Sift	Benign	0.26	T;T;T;T;.
Sift4G	Benign	0.38	T;T;T;T;T
Polyphen		0.51	P;.;.;P;.
Vest4		0.60
MutPred		0.53		Loss of catalytic residue at V27 (P = 0.0149);Loss of catalytic residue at V27 (P = 0.0149);Loss of catalytic residue at V27 (P = 0.0149);Loss of catalytic residue at V27 (P = 0.0149);Loss of catalytic residue at V27 (P = 0.0149);
MVP		0.66
MPC		1.2
ClinPred		0.70	D
GERP RS		5.6
Varity_R		0.42
gMVP		0.87

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: rs1411095348; hg19: chr14-35468778;