NM_003136.4:c.79-132C>T

Variant names:

• chr14-34999426-C-T
• rs28627922
• NM_003136.4:c.79-132C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003136.4(SRP54):​c.79-132C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 588,948 control chromosomes in the GnomAD database, including 49,588 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (10918 hom., cov: 31)
  • Exomes 𝑓: 0.41 (38670 hom.)
• Consequence: SRP54 NM_003136.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.117
• Publications: 3 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 14-34999426-C-T is Benign according to our data. Variant chr14-34999426-C-T is described in ClinVar as Benign. ClinVar VariationId is 1294954.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRP54	NM_003136.4	MANE Select	c.79-132C>T		intron	N/A	NP_003127.1	P61011-1
	SRP54	NM_001440813.1		c.79-132C>T		intron	N/A	NP_001427742.1
	SRP54	NM_001146282.2		c.24-1510C>T		intron	N/A	NP_001139754.1	P61011-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRP54	ENST00000216774.11	TSL:1 MANE Select	c.79-132C>T		intron	N/A	ENSP00000216774.6	P61011-1
	SRP54	ENST00000859405.1		c.79-132C>T		intron	N/A	ENSP00000529464.1
	SRP54	ENST00000556994.5	TSL:5	c.79-132C>T		intron	N/A	ENSP00000451818.1	P61011-1

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55921 AN: 151792 Hom.: 10909 Cov.: 31

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.364

GnomAD4 exome AF: 0.406 AC: 177286 AN: 437038 Hom.: 38670 AF XY: 0.406 AC XY: 93843 AN XY: 230864

African (AFR) AF: 0.273 AC: 3450 AN: 12660

American (AMR) AF: 0.330 AC: 6048 AN: 18326

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 4800 AN: 12544

East Asian (EAS) AF: 0.737 AC: 22912 AN: 31108

South Asian (SAS) AF: 0.430 AC: 16639 AN: 38676

European-Finnish (FIN) AF: 0.477 AC: 14039 AN: 29410

Middle Eastern (MID) AF: 0.334 AC: 600 AN: 1794

European-Non Finnish (NFE) AF: 0.370 AC: 99268 AN: 268038

Other (OTH) AF: 0.389 AC: 9530 AN: 24482

GnomAD4 genome AF: 0.368 AC: 55967 AN: 151910 Hom.: 10918 Cov.: 31 AF XY: 0.378 AC XY: 28046 AN XY: 74240

African (AFR) AF: 0.278 AC: 11516 AN: 41402

American (AMR) AF: 0.359 AC: 5484 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1323 AN: 3472

East Asian (EAS) AF: 0.689 AC: 3566 AN: 5172

South Asian (SAS) AF: 0.442 AC: 2131 AN: 4818

European-Finnish (FIN) AF: 0.488 AC: 5139 AN: 10538

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.378 AC: 25715 AN: 67940

Other (OTH) AF: 0.368 AC: 775 AN: 2106

Alfa AF: 0.363 Hom.: 1322

Bravo AF: 0.353

Asia WGS AF: 0.556 AC: 1931 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.9
DANN	Benign	0.19
PhyloP100		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28627922; hg19: chr14-35468632;