4-56467637-T-C

Position:

• chr4-56467637-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 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

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRP72	NM_006947.4	c.2T>C	p.Met1?	start_lost	1/19	ENST00000642900.1	NP_008878.3
SRP72	NM_001267722.2	c.2T>C	p.Met1?	start_lost	1/17		NP_001254651.1
SRP72	XM_024454192.2	c.2T>C	p.Met1?	start_lost	1/17		XP_024309960.1
SRP72	NR_151856.2	n.21T>C		non_coding_transcript_exon_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRP72	ENST00000642900.1	c.2T>C	p.Met1?	start_lost	1/19		NM_006947.4	ENSP00000495128	P1
SRP72	ENST00000510663.6	c.2T>C	p.Met1?	start_lost	1/17	1		ENSP00000424576
SRP72	ENST00000504757.2	c.2T>C	p.Met1?	start_lost	1/5	2		ENSP00000473576

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.21e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 07, 2023

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
MutationTaster	Benign	1.0	D;D
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.93
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-57333803;