14-35007368-AAAC-A

Position:

• chr14-35007368-AAAC-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_003136.4(SRP54):​c.349_351del​(p.Thr117del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRP54 NM_003136.4 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 9.19

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 13 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 NM_003136.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_003136.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 14-35007368-AAAC-A is Pathogenic according to our data. Variant chr14-35007368-AAAC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-35007368-AAAC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRP54	NM_003136.4	c.349_351del	p.Thr117del	inframe_deletion	5/16	ENST00000216774.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRP54	ENST00000216774.11	c.349_351del	p.Thr117del	inframe_deletion	5/16	1	NM_003136.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neutropenia, severe congenital, 8, autosomal dominant Pathogenic:5 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 05, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 31, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Mar 01, 2023	The inframe deletion c.349_351del (p.Thr117del) variant in SRP54 gene has been previously reported in heterozygous state in multiple individuals affected with Severe Congenital Neutropenia (Carapito et al., 2017; Bellanné-Chantelot et al., 2018; Carden et al., 2018). Experimental studies indicate that this variant affects SRP54 function (Carapito et al., 2017). The p.Thr117del variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). This p.Thr117del causes deletion of amino acid Threonine at position 117. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, dominant-negative is the suggested mechanism (PMID: 33227812). (I) 0107 - This gene is associated with autosomal dominant disease. Variants expected to interact with the G1 element of the GTPase domain are associated with severe congenital neutropenia 8 (MIM#618752), while variants located elsewhere are associated with Shwachman-Diamond syndrome, SRP54-related (MONDO#0009833) (PMID: 29914977). (I) 0214 - In-frame insertion/deletion fully contained in a repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated GTPase domain (PMID: 29914977). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is a recurrent variant reported in several individuals with chronic neutropenia, including de novo events (PMID: 29914977; ClinVar). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Jun 07, 2020	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2022	Not observed in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; Published functional studies suggest a damaging effect (Carapito et al., 2017); This variant is associated with the following publications: (PMID: 28972538, 29956078, 29914977, 32277798, 32196641, 32135276, 32054657, 33726816, 33053321) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	This variant, c.349_351del, results in the deletion of 1 amino acid(s) of the SRP54 protein (p.Thr117del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with congenital neutropenia and Shwachman-Diamond-like syndrome (PMID: 28972538, 29914977, 29956078). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 430852). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SRP54 function (PMID: 28972538). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2018	- -

Shwachman-Diamond syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Jul 14, 2017

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555354198; hg19: chr14-35476574;