rs1555354750

Positions:

• chr14-35013386-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_003136.4(SRP54):​c.677G>A​(p.Gly226Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRP54 NM_003136.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a helix (size 5) in uniprot entity SRP54_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003136.4
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 14-35013386-G-A is Pathogenic according to our data. Variant chr14-35013386-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430850.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-35013386-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRP54	NM_003136.4	c.677G>A	p.Gly226Glu	missense_variant	9/16	ENST00000216774.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRP54	ENST00000216774.11	c.677G>A	p.Gly226Glu	missense_variant	9/16	1	NM_003136.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neutropenia, severe congenital, 8, autosomal dominant Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 31, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2017

- -

Shwachman-Diamond syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Molecular ImmunoRheumatology UMRS_1109, Institut national de la santé et de la recherche médicale

Jul 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;D;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	5.2	H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.7	D;D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.027	D;D;D;D
Polyphen		0.79	P;.;P;.
Vest4		0.96
MutPred		0.93		Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);.;
MVP		0.56
MPC		2.3
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.98
gMVP		0.98

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: rs1555354750; hg19: chr14-35482592;