4-56467651-A-G

Variant names:

• chr4-56467651-A-G
• rs758030928
• NM_006947.4:c.16A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_006947.4(SRP72):​c.16A>G​(p.Ser6Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,406,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S6T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SRP72 NM_006947.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.585
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03897196).
• BP6: Variant 4-56467651-A-G is Benign according to our data. Variant chr4-56467651-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3962140.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRP72	NM_006947.4	c.16A>G	p.Ser6Gly	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.16A>G	p.Ser6Gly	missense_variant	Exon 1 of 19		NM_006947.4	ENSP00000495128.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1406960 Hom.: 0 Cov.: 29 AF XY: 0.00000143 AC XY: 1 AN XY: 698698

African (AFR) AF: 0.00 AC: 0 AN: 29832

American (AMR) AF: 0.00 AC: 0 AN: 35416

Ashkenazi Jewish (ASJ) AF: 0.0000409 AC: 1 AN: 24472

East Asian (EAS) AF: 0.00 AC: 0 AN: 34444

South Asian (SAS) AF: 0.00 AC: 0 AN: 80586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1086426

Other (OTH) AF: 0.00 AC: 0 AN: 57890

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jun 07, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.91
DEOGEN2	Benign	0.038	T;.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.25	T;T;.;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.039	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.3	N;N;N;.
PhyloP100		0.58
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N;N;.;.
REVEL	Benign	0.22
Sift	Benign	0.10	T;T;.;.
Sift4G	Benign	0.45	T;T;.;T
Polyphen		0.0	B;.;B;.
Vest4		0.13
MutPred		0.23		Loss of glycosylation at S6 (P = 7e-04);Loss of glycosylation at S6 (P = 7e-04);Loss of glycosylation at S6 (P = 7e-04);Loss of glycosylation at S6 (P = 7e-04);
MVP		0.42
MPC		0.20
ClinPred		0.088	T
GERP RS		-2.5
PromoterAI		-0.023	Neutral
Varity_R		0.089
gMVP		0.090
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs758030928; hg19: chr4-57333817;