4-56467693-C-T

Position:

• chr4-56467693-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP4_Strong BP6_Very_Strong BS2

The NM_006947.4(SRP72):​c.58C>T​(p.Arg20Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00408 in 1,554,546 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0042 (19 hom.)
• Consequence: SRP72 NM_006947.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.75

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]

SRP72 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, FATHMM_MKL, PROVEAN [when BayesDel_addAF, max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.01167652).
• BP6: Variant 4-56467693-C-T is Benign according to our data. Variant chr4-56467693-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 349117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-56467693-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 440 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRP72	NM_006947.4	c.58C>T	p.Arg20Trp	missense_variant	1/19	ENST00000642900.1	NP_008878.3
SRP72	NM_001267722.2	c.58C>T	p.Arg20Trp	missense_variant	1/17		NP_001254651.1
SRP72	XM_024454192.2	c.58C>T	p.Arg20Trp	missense_variant	1/17		XP_024309960.1
SRP72	NR_151856.2	n.77C>T		non_coding_transcript_exon_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRP72	ENST00000642900.1	c.58C>T	p.Arg20Trp	missense_variant	1/19		NM_006947.4	ENSP00000495128.1
SRP72	ENST00000510663.6	c.58C>T	p.Arg20Trp	missense_variant	1/17	1		ENSP00000424576.1
SRP72	ENST00000504757.2	c.58C>T	p.Arg20Trp	missense_variant	1/5	2		ENSP00000473576.1
SRP72	ENST00000505314.2	c.-45C>T		upstream_gene_variant		3		ENSP00000425190.3

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 440 AN: 150982 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000950

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00276

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00189

Gnomad FIN AF: 0.000777

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00485

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00260 AC: 534 AN: 205648 Hom.: 0 AF XY: 0.00277 AC XY: 314 AN XY: 113308

Gnomad AFR exome AF: 0.000926

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.000916

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00130

Gnomad FIN exome AF: 0.000949

Gnomad NFE exome AF: 0.00428

Gnomad OTH exome AF: 0.00284

GnomAD4 exome AF: 0.00421 AC: 5909 AN: 1403452 Hom.: 19 Cov.: 33 AF XY: 0.00412 AC XY: 2874 AN XY: 697408

Gnomad4 AFR exome AF: 0.000911

Gnomad4 AMR exome AF: 0.00205

Gnomad4 ASJ exome AF: 0.000652

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00190

Gnomad4 FIN exome AF: 0.00139

Gnomad4 NFE exome AF: 0.00494

Gnomad4 OTH exome AF: 0.00352

GnomAD4 genome AF: 0.00291 AC: 440 AN: 151094 Hom.: 1 Cov.: 31 AF XY: 0.00272 AC XY: 201 AN XY: 73792

Gnomad4 AFR AF: 0.000947

Gnomad4 AMR AF: 0.00276

Gnomad4 ASJ AF: 0.00145

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00189

Gnomad4 FIN AF: 0.000777

Gnomad4 NFE AF: 0.00485

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00383 Hom.: 5

Bravo AF: 0.00305

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00269 AC: 327

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	SRP72: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 24, 2019

- -

SRP72-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal dominant aplasia and myelodysplasia Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T;.;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.91	D;D;.;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.6	M;M;M;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.3	D;D;.;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;.;D
Polyphen		1.0	D;.;D;.
Vest4		0.62
MVP		0.68
MPC		0.54
ClinPred		0.035	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.56

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: rs111673705; hg19: chr4-57333859;