4-56467654-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006947.4(SRP72):c.19G>T(p.Gly7Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00179 in 1,556,654 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G7E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (11 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (49 hom.)
• Consequence: SRP72 NM_006947.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.46

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047951043).
• BP6: Variant 4-56467654-G-T is Benign according to our data. Variant chr4-56467654-G-T is described in ClinVar as [Benign]. Clinvar id is 349112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRP72	NM_006947.4	c.19G>T	p.Gly7Trp	missense_variant	1/19	ENST00000642900.1
SRP72	NM_001267722.2	c.19G>T	p.Gly7Trp	missense_variant	1/17
SRP72	XM_024454192.2	c.19G>T	p.Gly7Trp	missense_variant	1/17
SRP72	NR_151856.2	n.38G>T		non_coding_transcript_exon_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRP72	ENST00000642900.1	c.19G>T	p.Gly7Trp	missense_variant	1/19		NM_006947.4	P1
SRP72	ENST00000510663.6	c.19G>T	p.Gly7Trp	missense_variant	1/17	1
SRP72	ENST00000504757.2	c.19G>T	p.Gly7Trp	missense_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 411 AN: 152090 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.0626

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00489 AC: 965 AN: 197496 Hom.: 33 AF XY: 0.00429 AC XY: 470 AN XY: 109684

Gnomad AFR exome AF: 0.000722

Gnomad AMR exome AF: 0.000246

Gnomad ASJ exome AF: 0.00694

Gnomad EAS exome AF: 0.0718

Gnomad SAS exome AF: 0.000829

Gnomad FIN exome AF: 0.0000485

Gnomad NFE exome AF: 0.000109

Gnomad OTH exome AF: 0.00254

GnomAD4 exome AF: 0.00169 AC: 2368 AN: 1404446 Hom.: 49 Cov.: 30 AF XY: 0.00162 AC XY: 1127 AN XY: 697194

Gnomad4 AFR exome AF: 0.000336

Gnomad4 AMR exome AF: 0.000281

Gnomad4 ASJ exome AF: 0.00760

Gnomad4 EAS exome AF: 0.0512

Gnomad4 SAS exome AF: 0.000960

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.0000747

Gnomad4 OTH exome AF: 0.00424

GnomAD4 genome AF: 0.00271 AC: 413 AN: 152208 Hom.: 11 Cov.: 31 AF XY: 0.00297 AC XY: 221 AN XY: 74408

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.0630

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00342

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00561 AC: 679

Asia WGS AF: 0.0210 AC: 74 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2019	- -

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	0.65
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Benign	0.051	T;.;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.83	T;T;.;T
MetaRNN	Benign	0.0048	T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.1	M;M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.1	N;N;.;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0070	D;D;.;.
Sift4G	Uncertain	0.011	D;D;.;D
Polyphen		0.98	D;.;D;.
Vest4		0.36
MVP		0.90
MPC		0.89
ClinPred		0.034	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.12
gMVP		0.34

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: rs17524437; hg19: chr4-57333820; COSMIC: COSV61379029; COSMIC: COSV61379029;