rs12433712

Variant names:

• chr14-34999687-T-A
• rs12433712
• NM_003136.4:c.170+38T>A

Your query was ambiguous. Multiple possible variants found:

• chr14-34999687-T-A
• chr14-34999687-T-C
• chr14-34999687-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003136.4(SRP54):​c.170+38T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 1,447,684 control chromosomes in the GnomAD database, including 112,805 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10921 hom., cov: 31)
  • Exomes 𝑓: 0.39 (101884 hom.)
• Consequence: SRP54 NM_003136.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.486
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 14-34999687-T-A is Benign according to our data. Variant chr14-34999687-T-A is described in ClinVar as Benign. ClinVar VariationId is 1232103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRP54	NM_003136.4	c.170+38T>A		intron_variant	Intron 3 of 15	ENST00000216774.11	NP_003127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRP54	ENST00000216774.11	c.170+38T>A		intron_variant	Intron 3 of 15	1	NM_003136.4	ENSP00000216774.6

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55912 AN: 151810 Hom.: 10912 Cov.: 31

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.338

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.365

GnomAD2 exomes AF: 0.402 AC: 99233 AN: 247028 AF XY: 0.404

Gnomad AFR exome AF: 0.275

Gnomad AMR exome AF: 0.322

Gnomad ASJ exome AF: 0.390

Gnomad EAS exome AF: 0.688

Gnomad FIN exome AF: 0.487

Gnomad NFE exome AF: 0.373

Gnomad OTH exome AF: 0.376

GnomAD4 exome AF: 0.389 AC: 504154 AN: 1295756 Hom.: 101884 Cov.: 17 AF XY: 0.391 AC XY: 255272 AN XY: 653182

African (AFR) AF: 0.271 AC: 8175 AN: 30128

American (AMR) AF: 0.325 AC: 14148 AN: 43570

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 9571 AN: 24870

East Asian (EAS) AF: 0.729 AC: 28326 AN: 38842

South Asian (SAS) AF: 0.437 AC: 35970 AN: 82302

European-Finnish (FIN) AF: 0.482 AC: 25274 AN: 52412

Middle Eastern (MID) AF: 0.339 AC: 1839 AN: 5432

European-Non Finnish (NFE) AF: 0.373 AC: 359379 AN: 963416

Other (OTH) AF: 0.392 AC: 21472 AN: 54784

GnomAD4 genome AF: 0.368 AC: 55958 AN: 151928 Hom.: 10921 Cov.: 31 AF XY: 0.378 AC XY: 28035 AN XY: 74226

African (AFR) AF: 0.278 AC: 11547 AN: 41470

American (AMR) AF: 0.359 AC: 5490 AN: 15272

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

East Asian (EAS) AF: 0.689 AC: 3549 AN: 5148

South Asian (SAS) AF: 0.441 AC: 2122 AN: 4810

European-Finnish (FIN) AF: 0.488 AC: 5141 AN: 10530

Middle Eastern (MID) AF: 0.339 AC: 99 AN: 292

European-Non Finnish (NFE) AF: 0.378 AC: 25691 AN: 67918

Other (OTH) AF: 0.368 AC: 776 AN: 2106

Alfa AF: 0.299 Hom.: 1225

Bravo AF: 0.353

Asia WGS AF: 0.556 AC: 1931 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 16, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.3
DANN	Benign	0.53
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs12433712; hg19: chr14-35468893;