rs1578170315

Variant names:

• chr4-56467637-T-C
• rs1578170315
• NM_006947.4:c.2T>C

Your query was ambiguous. Multiple possible variants found:

• chr4-56467637-T-C
• chr4-56467637-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_006947.4(SRP72):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000711 in 1,406,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SRP72 NM_006947.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.73
• 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 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 196 codons. Genomic position: 56474367. Lost 0.291 part of the original CDS.
• 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.2T>C	p.Met1?	start_lost	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.2T>C	p.Met1?	start_lost	Exon 1 of 19		NM_006947.4	ENSP00000495128.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406294 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 697788

African (AFR) AF: 0.00 AC: 0 AN: 29992

American (AMR) AF: 0.00 AC: 0 AN: 35296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24396

East Asian (EAS) AF: 0.00 AC: 0 AN: 34616

South Asian (SAS) AF: 0.00 AC: 0 AN: 80402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52324

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

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085778

Other (OTH) AF: 0.00 AC: 0 AN: 57874

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 07, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; Initiation codon variant in a gene for which loss-of-function is not a known mechanism of disease -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T;.;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;D;.;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.13	D
PhyloP100		6.7
PROVEAN	Uncertain	-2.5	N;N;.;.
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		0.72	P;.;P;.
Vest4		0.91
MutPred		1.0		Gain of glycosylation at M1 (P = 0.0103);Gain of glycosylation at M1 (P = 0.0103);Gain of glycosylation at M1 (P = 0.0103);Gain of glycosylation at M1 (P = 0.0103);
MVP		0.86
ClinPred		0.99	D
GERP RS		5.7
PromoterAI		-0.86	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.93
gMVP		0.53
Mutation Taster		=24/176	disease causing

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: rs1578170315; hg19: chr4-57333803;