rs139502866

chr4-56467655-G-Achr4-56467655-G-Cchr4-56467655-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006947.4(SRP72):c.20G>A(p.Gly7Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,561,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G7A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: SRP72 NM_006947.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.24

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20868775).
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRP72	NM_006947.4	c.20G>A	p.Gly7Glu	missense_variant	1/19	ENST00000642900.1
SRP72	NM_001267722.2	c.20G>A	p.Gly7Glu	missense_variant	1/17
SRP72	XM_024454192.2	c.20G>A	p.Gly7Glu	missense_variant	1/17
SRP72	NR_151856.2	n.39G>A		non_coding_transcript_exon_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRP72	ENST00000642900.1	c.20G>A	p.Gly7Glu	missense_variant	1/19		NM_006947.4	P1
SRP72	ENST00000510663.6	c.20G>A	p.Gly7Glu	missense_variant	1/17	1
SRP72	ENST00000504757.2	c.20G>A	p.Gly7Glu	missense_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152140 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000115 AC: 23 AN: 199632 Hom.: 0 AF XY: 0.000135 AC XY: 15 AN XY: 110750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000122

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000226

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000114 AC: 160 AN: 1409242 Hom.: 0 Cov.: 30 AF XY: 0.000129 AC XY: 90 AN XY: 699872

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000279

Gnomad4 ASJ exome AF: 0.0000407

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.0000345

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152140 Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6 AN XY: 74314

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000720 Hom.: 0

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 09, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 20, 2023	The c.20G>A (p.G7E) alteration is located in exon 1 (coding exon 1) of the SRP72 gene. This alteration results from a G to A substitution at nucleotide position 20, causing the glycine (G) at amino acid position 7 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 7 of the SRP72 protein (p.Gly7Glu). This variant is present in population databases (rs139502866, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SRP72-related conditions. ClinVar contains an entry for this variant (Variation ID: 349113). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Autosomal dominant aplasia and myelodysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	Uncertain	0.55
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.018	T;.;T;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.083
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.82	T;T;.;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.1	M;M;M;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.45	N;N;.;.
REVEL	Uncertain	0.36
Sift	Benign	0.10	T;T;.;.
Sift4G	Benign	0.58	T;T;.;T
Polyphen		0.35	B;.;B;.
Vest4		0.22
MutPred		0.18		Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);
MVP		0.81
MPC		0.58
ClinPred		0.84	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.076
gMVP		0.28

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: rs139502866; hg19: chr4-57333821;