Genetic Variant SRP72:p.Ser6Arg (chr4-56467653-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006947.4(SRP72):c.18C>A(p.Ser6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. 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: 7.1e-7 ( 0 hom. )

Consequence

SRP72
NM_006947.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.01

Publications

0 publications found

Variant links:

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

SRP72 links:

ENSG00000289393 (HGNC:):

ENSG00000289393 links:

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ACMG classification

Classification was made for transcript

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=0.07736239).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRP72	NM_006947.4 link	c.18C>A	p.Ser6Arg	missense_variant	Exon 1 of 19	ENST00000642900.1	NP_008878.3	O76094-1V9HWK0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRP72	ENST00000642900.1 link	c.18C>A	p.Ser6Arg	missense_variant	Exon 1 of 19		NM_006947.4	ENSP00000495128.1		O76094-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399356

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

694704

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29592

American (AMR)

AF:

0.00

AC:

AN:

35234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24186

East Asian (EAS)

AF:

0.00

AC:

AN:

34008

South Asian (SAS)

AF:

0.00

AC:

AN:

80204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51538

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5576

European-Non Finnish (NFE)

AF:

9.25e-7

AC:

AN:

1081606

Other (OTH)

AF:

0.00

AC:

AN:

57412

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.029

T;.;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.22

T;T;.;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.077

T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.90

L;L;L;.

PhyloP100

-1.0

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.3

N;N;.;.

REVEL

Benign

0.21

Sift

Uncertain

0.019

D;D;.;.

Sift4G

Benign

0.094

T;T;.;D

Polyphen

0.31

B;.;B;.

Vest4

0.12

MutPred

0.36

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

0.43

MPC

0.27

ClinPred

0.28

GERP RS

-2.6

PromoterAI

-0.00020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.21

gMVP

0.13

Mutation Taster

=85/15

polymorphism

(source)

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

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4-56467653-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over