Variant rs1555354200 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The ENST00000216774.11(SRP54):c.343A>G(p.Thr115Ala) 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 Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SRP54
ENST00000216774.11 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2O:1

Conservation

PhyloP100: 9.19

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a binding_site (size 7) in uniprot entity SRP54_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in ENST00000216774.11

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, 0.984

PP5

Variant 14-35007370-A-G is Pathogenic according to our data. Variant chr14-35007370-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 430851.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-35007370-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRP54	NM_003136.4 linkuse as main transcript	c.343A>G	p.Thr115Ala	missense_variant	5/16	ENST00000216774.11	NP_003127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRP54	ENST00000216774.11 linkuse as main transcript	c.343A>G	p.Thr115Ala	missense_variant	5/16	1	NM_003136.4	ENSP00000216774	P1	P61011-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1435214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

714264

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Neutropenia, severe congenital, 8, autosomal dominant

Pathogenic:1Other:1

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

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

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;.;D;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

.;D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

5.2

H;.;H;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.7

D;D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.92

MutPred

0.95

Loss of methylation at K120 (P = 0.0517);.;Loss of methylation at K120 (P = 0.0517);.;

MVP

0.78

MPC

2.2

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.87

gMVP

0.97

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over