Genetic Variant SRP72:p.Ala291Glu (chr4-56483185-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006947.4(SRP72):c.872C>A(p.Ala291Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,611,350 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. A291V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SRP72
NM_006947.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.82

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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.872C>A	p.Ala291Glu	missense_variant	Exon 9 of 19	ENST00000642900.1	NP_008878.3	O76094-1V9HWK0
SRP72	NM_001267722.2 link	c.689C>A	p.Ala230Glu	missense_variant	Exon 7 of 17		NP_001254651.1	O76094-2
SRP72	XM_024454192.2 link	c.872C>A	p.Ala291Glu	missense_variant	Exon 9 of 17		XP_024309960.1
SRP72	NR_151856.2 link	n.891C>A		non_coding_transcript_exon_variant	Exon 9 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SRP72	ENST00000642900.1 link	c.872C>A	p.Ala291Glu	missense_variant	Exon 9 of 19		NM_006947.4	ENSP00000495128.1	O76094-1
SRP72	ENST00000510663.6 link	c.689C>A	p.Ala230Glu	missense_variant	Exon 7 of 17	1		ENSP00000424576.1	O76094-2
SRP72	ENST00000505314.2 link	c.724-1551C>A		intron_variant	Intron 8 of 11	3		ENSP00000425190.3	D6RDY6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459246

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725948

show subpopulations

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.052

T;.;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;.

M_CAP

Benign

0.040

MetaRNN

Uncertain

0.56

D;D;D

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.3

M;.;M

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.1

N;D;.

REVEL

Uncertain

0.38

Sift

Benign

0.043

D;D;.

Sift4G

Benign

0.16

T;T;.

Polyphen

0.95

P;.;P

Vest4

0.70

MutPred

0.45

Gain of disorder (P = 0.0154);.;Gain of disorder (P = 0.0154);

MVP

0.87

MPC

0.76

ClinPred

0.97

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

gMVP

0.55

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over