14-35022137-T-A

Variant names:

• chr14-35022137-T-A
• rs9322942
• NM_003136.4:c.1157-773T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003136.4(SRP54):​c.1157-773T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 151,694 control chromosomes in the GnomAD database, including 9,629 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (9629 hom., cov: 31)
• Consequence: SRP54 NM_003136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.423
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRP54	NM_003136.4	c.1157-773T>A		intron_variant	Intron 13 of 15	ENST00000216774.11	NP_003127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRP54	ENST00000216774.11	c.1157-773T>A		intron_variant	Intron 13 of 15	1	NM_003136.4	ENSP00000216774.6

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52324 AN: 151580 Hom.: 9622 Cov.: 31

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.420

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.345

Gnomad OTH AF: 0.339

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

GnomAD4 genome AF: 0.345 AC: 52369 AN: 151694 Hom.: 9629 Cov.: 31 AF XY: 0.354 AC XY: 26242 AN XY: 74048

African (AFR) AF: 0.273 AC: 11289 AN: 41356

American (AMR) AF: 0.334 AC: 5084 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1159 AN: 3472

East Asian (EAS) AF: 0.690 AC: 3543 AN: 5132

South Asian (SAS) AF: 0.419 AC: 2020 AN: 4816

European-Finnish (FIN) AF: 0.462 AC: 4833 AN: 10452

Middle Eastern (MID) AF: 0.286 AC: 83 AN: 290

European-Non Finnish (NFE) AF: 0.345 AC: 23471 AN: 67954

Other (OTH) AF: 0.343 AC: 721 AN: 2104

Alfa AF: 0.339 Hom.: 1093

Bravo AF: 0.331

Asia WGS AF: 0.544 AC: 1889 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	8.2
DANN	Benign	0.68
PhyloP100		0.42
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: rs9322942; hg19: chr14-35491343;