4-56467640-C-T

Variant names:

• chr4-56467640-C-T
• rs1719782095
• NM_006947.4:c.5C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_006947.4(SRP72):​c.5C>T​(p.Ala2Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000712 in 1,404,596 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SRP72 NM_006947.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.64
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant aplasia and myelodysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• acute myeloid leukemia

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ENSG00000289393 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a modified_residue N-acetylalanine (size 0) in uniprot entity SRP72_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRP72	NM_006947.4	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 19	ENST00000642900.1	NP_008878.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRP72	ENST00000642900.1	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 19		NM_006947.4	ENSP00000495128.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1404596 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 696876

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29886

American (AMR) AF: 0.00 AC: 0 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24292

East Asian (EAS) AF: 0.00 AC: 0 AN: 34494

South Asian (SAS) AF: 0.00 AC: 0 AN: 80188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1084890

Other (OTH) AF: 0.00 AC: 0 AN: 57794

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A2V variant (also known as c.5C>T), located in coding exon 1 of the SRP72 gene, results from a C to T substitution at nucleotide position 5. The alanine at codon 2 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.037	T;.;T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.80	T;T;.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.9	M;M;M;.
PhyloP100		6.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.7	N;N;.;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0070	D;D;.;.
Sift4G	Benign	0.11	T;T;.;T
Polyphen		1.0	D;.;D;.
Vest4		0.46
MutPred		0.12		Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);
MVP		0.88
MPC		0.79
ClinPred		0.98	D
GERP RS		5.7
PromoterAI		-0.66	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.19
gMVP		0.51
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1719782095; hg19: chr4-57333806;