Genetic Variant SRP72:p.Ala2Gly (chr4-56467640-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_006947.4(SRP72):c.5C>G(p.Ala2Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000712 in 1,404,598 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2V) 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: 6.64

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 4 ACMG points.

PM1

In a modified_residue N-acetylalanine (size 0) in uniprot entity SRP72_HUMAN

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 link	c.5C>G	p.Ala2Gly	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.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 19		NM_006947.4	ENSP00000495128.1		O76094-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.12e-7

AC:

AN:

1404598

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

696876

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29886

American (AMR)

AF:

0.00

AC:

AN:

35194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24292

East Asian (EAS)

AF:

0.00

AC:

AN:

34494

South Asian (SAS)

AF:

0.00

AC:

AN:

80188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5618

European-Non Finnish (NFE)

AF:

9.22e-7

AC:

AN:

1084892

Other (OTH)

AF:

0.00

AC:

AN:

57794

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

Benign

0.071

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.052

T;.;T;T

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.74

T;T;.;T

M_CAP

Benign

0.077

MetaRNN

Uncertain

0.47

T;T;T;T

MetaSVM

Uncertain

-0.015

MutationAssessor

Benign

1.6

L;L;L;.

PhyloP100

6.6

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.9

N;N;.;.

REVEL

Benign

0.26

Sift

Uncertain

0.023

D;D;.;.

Sift4G

Benign

0.24

T;T;.;T

Polyphen

0.99

D;.;D;.

Vest4

0.42

MutPred

0.10

Loss of stability (P = 0.1);Loss of stability (P = 0.1);Loss of stability (P = 0.1);Loss of stability (P = 0.1);

MVP

0.86

MPC

0.81

ClinPred

0.98

GERP RS

5.7

PromoterAI

-0.76

Under-expression

(source)

Varity_R

0.22

gMVP

0.38

Mutation Taster

=55/45

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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4-56467640-C-G

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