4-56467656-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006947.4(SRP72):c.21G>T(p.Gly7=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,555,988 control chromosomes in the GnomAD database, including 35,055 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G7G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.19 (3286 hom., cov: 31)
  • Exomes 𝑓: 0.21 (31769 hom.)
• Consequence: SRP72 NM_006947.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.112

Genes affected

SRP72 (HGNC:11303): (signal recognition particle 72) This gene encodes the 72 kDa subunit of the signal recognition particle (SRP), a ribonucleoprotein complex that mediates the targeting of secretory proteins to the endoplasmic reticulum (ER). The SRP complex consists of a 7S RNA and 6 protein subunits: SRP9, SRP14, SRP19, SRP54, SRP68, and SRP72, that are bound to the 7S RNA as monomers or heterodimers. SRP has at least 3 distinct functions that can be associated with the protein subunits: signal recognition, translational arrest, and ER membrane targeting by interaction with the docking protein. Mutations in this gene are associated with familial bone marrow failure. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 4-56467656-G-T is Benign according to our data. Variant chr4-56467656-G-T is described in ClinVar as [Benign]. Clinvar id is 349114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-56467656-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.112 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRP72	NM_006947.4	c.21G>T	p.Gly7=	synonymous_variant	1/19	ENST00000642900.1
SRP72	NM_001267722.2	c.21G>T	p.Gly7=	synonymous_variant	1/17
SRP72	XM_024454192.2	c.21G>T	p.Gly7=	synonymous_variant	1/17
SRP72	NR_151856.2	n.40G>T		non_coding_transcript_exon_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRP72	ENST00000642900.1	c.21G>T	p.Gly7=	synonymous_variant	1/19		NM_006947.4	P1
SRP72	ENST00000510663.6	c.21G>T	p.Gly7=	synonymous_variant	1/17	1
SRP72	ENST00000504757.2	c.21G>T	p.Gly7=	synonymous_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29544 AN: 151828 Hom.: 3272 Cov.: 31

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.231

GnomAD3 exomes AF: 0.232 AC: 45960 AN: 197836 Hom.: 6443 AF XY: 0.224 AC XY: 24645 AN XY: 109860

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.474

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.199

Gnomad SAS exome AF: 0.254

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.191

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.205 AC: 288364 AN: 1404042 Hom.: 31769 Cov.: 32 AF XY: 0.205 AC XY: 143168 AN XY: 697074

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.451

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.208

Gnomad4 SAS exome AF: 0.253

Gnomad4 FIN exome AF: 0.241

Gnomad4 NFE exome AF: 0.197

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.195 AC: 29571 AN: 151946 Hom.: 3286 Cov.: 31 AF XY: 0.201 AC XY: 14955 AN XY: 74268

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.352

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.195

Gnomad4 SAS AF: 0.260

Gnomad4 FIN AF: 0.238

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.234

Alfa AF: 0.168 Hom.: 1181

Bravo AF: 0.200

Asia WGS AF: 0.266 AC: 924 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant aplasia and myelodysplasia Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 30, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	7.9
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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

Publications

LitVar

Other links and lift over

dbSNP: rs12513091; hg19: chr4-57333822; COSMIC: COSV61377564; COSMIC: COSV61377564;