4-56467652-G-C

Variant names:

• chr4-56467652-G-C
• rs1473458044
• NM_006947.4:c.17G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006947.4(SRP72):​c.17G>C​(p.Ser6Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000071 in 1,408,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S6G) has been classified as Likely benign.

• 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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.50
• 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, Orphanet, Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

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

ENSG00000289393 (HGNC:58796):

LOC124900706 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10458416).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006947.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRP72	NM_006947.4	MANE Select	c.17G>C	p.Ser6Thr	missense	Exon 1 of 19	NP_008878.3
	SRP72	NM_001267722.2		c.17G>C	p.Ser6Thr	missense	Exon 1 of 17	NP_001254651.1	O76094-2
	SRP72	NR_151856.2		n.36G>C		non_coding_transcript_exon	Exon 1 of 20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRP72	ENST00000642900.1	MANE Select	c.17G>C	p.Ser6Thr	missense	Exon 1 of 19	ENSP00000495128.1	O76094-1
	SRP72	ENST00000510663.6	TSL:1	c.17G>C	p.Ser6Thr	missense	Exon 1 of 17	ENSP00000424576.1	O76094-2
	SRP72	ENST00000925431.1		c.17G>C	p.Ser6Thr	missense	Exon 1 of 19	ENSP00000595490.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000502 AC: 1 AN: 199244 AF XY: 0.00000902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408558 Hom.: 0 Cov.: 29 AF XY: 0.00000143 AC XY: 1 AN XY: 699496

⚠️ 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: 29878

American (AMR) AF: 0.00 AC: 0 AN: 35742

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24528

East Asian (EAS) AF: 0.00 AC: 0 AN: 34512

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5632

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087242

Other (OTH) AF: 0.00 AC: 0 AN: 57984

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.13	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.34	N
PhyloP100		5.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.18
Sift	Benign	0.26	T
Sift4G	Benign	0.49	T
Polyphen		0.067	B
Vest4		0.042
MutPred		0.20		Loss of glycosylation at S6 (P = 0.0098)
MVP		0.73
MPC		0.20
ClinPred		0.19	T
GERP RS		4.8
PromoterAI		-0.058	Neutral
Varity_R		0.18
gMVP		0.11
Mutation Taster		=93/7	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: rs1473458044; hg19: chr4-57333818;