chr4-56467653-C-CG

Position:

• chr4-56467653-C-CG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_006947.4(SRP72):​c.25dup​(p.Val9GlyfsTer9) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000374 in 1,550,684 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: SRP72 NM_006947.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U: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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRP72	NM_006947.4	c.25dup	p.Val9GlyfsTer9	frameshift_variant	1/19	ENST00000642900.1	NP_008878.3
SRP72	NM_001267722.2	c.25dup	p.Val9GlyfsTer9	frameshift_variant	1/17		NP_001254651.1
SRP72	XM_024454192.2	c.25dup	p.Val9GlyfsTer9	frameshift_variant	1/17		XP_024309960.1
SRP72	NR_151856.2	n.44dup		non_coding_transcript_exon_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRP72	ENST00000642900.1	c.25dup	p.Val9GlyfsTer9	frameshift_variant	1/19		NM_006947.4	ENSP00000495128	P1
SRP72	ENST00000510663.6	c.25dup	p.Val9GlyfsTer9	frameshift_variant	1/17	1		ENSP00000424576
SRP72	ENST00000504757.2	c.25dup	p.Val9GlyfsTer9	frameshift_variant	1/5	2		ENSP00000473576

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151404 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000485

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000393 AC: 55 AN: 1399280 Hom.: 0 Cov.: 30 AF XY: 0.0000360 AC XY: 25 AN XY: 694660

Gnomad4 AFR exome AF: 0.0000338

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.0000413

Gnomad4 EAS exome AF: 0.0000588

Gnomad4 SAS exome AF: 0.0000623

Gnomad4 FIN exome AF: 0.000175

Gnomad4 NFE exome AF: 0.0000305

Gnomad4 OTH exome AF: 0.0000348

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151404 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 73924

Gnomad4 AFR AF: 0.0000485

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change creates a premature translational stop signal (p.Val9Glyfs*9) in the SRP72 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SRP72 cause disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 1723735). 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	Aug 10, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not an established mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -

SRP72-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2024

The SRP72 c.25dupG variant is predicted to result in a frameshift and premature protein termination (p.Val9Glyfs*9). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of South Asian descent in gnomAD. Loss of function has not been conclusively established as a mechanism for SRP72-related disorders. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs763130641; hg19: chr4-57333819;