rs1555354198

Variant names:

• chr14-35007368-AAAC-A
• rs1555354198
• NM_003136.4:c.349_351delACA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_003136.4(SRP54):​c.349_351delACA​(p.Thr117del) variant causes a conservative 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T117T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRP54 NM_003136.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 9.19
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• neutropenia, severe congenital, 8, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant severe congenital neutropenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Shwachman-Diamond syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 430852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003136.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRP54	NM_003136.4	MANE Select	c.349_351delACA	p.Thr117del	conservative_inframe_deletion	Exon 5 of 16	NP_003127.1
	SRP54	NM_001440813.1		c.349_351delACA	p.Thr117del	conservative_inframe_deletion	Exon 5 of 16	NP_001427742.1
	SRP54	NM_001146282.2		c.202_204delACA	p.Thr68del	conservative_inframe_deletion	Exon 4 of 15	NP_001139754.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRP54	ENST00000216774.11	TSL:1 MANE Select	c.349_351delACA	p.Thr117del	conservative_inframe_deletion	Exon 5 of 16	ENSP00000216774.6
	SRP54	ENST00000556994.5	TSL:5	c.349_351delACA	p.Thr117del	conservative_inframe_deletion	Exon 6 of 17	ENSP00000451818.1
	SRP54	ENST00000677647.1		c.349_351delACA	p.Thr117del	conservative_inframe_deletion	Exon 5 of 16	ENSP00000504673.1

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

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Neutropenia, severe congenital, 8, autosomal dominant (7)
5	-	-	not provided (5)
1	-	-	Ciliary dyskinesia, primary, 40 (1)
1	-	-	Shwachman-Diamond syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2
Mutation Taster		=11/89	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555354198; hg19: chr14-35476574;