Genetic Variant SRP72:p.Gly7Ala (chr4-56467655-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006947.4(SRP72):c.20G>C(p.Gly7Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,561,500 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G7E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0073 ( 20 hom., cov: 31)

Exomes 𝑓: 0.00073 ( 12 hom. )

Consequence

SRP72
NM_006947.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.24

Publications

4 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, MODERATE, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
acute myeloid leukemia
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

SRP72 links:

ENSG00000289393 (HGNC:58796):

ENSG00000289393 links:

LOC124900706 (HGNC:):

LOC124900706 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0066815317).

BP6

Variant 4-56467655-G-C is Benign according to our data. Variant chr4-56467655-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0073 (1111/152254) while in subpopulation AFR AF = 0.0255 (1059/41550). AF 95% confidence interval is 0.0242. There are 20 homozygotes in GnomAd4. There are 515 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1111 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SRP72	NM_006947.4	MANE Select	c.20G>C	p.Gly7Ala	missense	Exon 1 of 19	NP_008878.3
SRP72	NM_001267722.2		c.20G>C	p.Gly7Ala	missense	Exon 1 of 17	NP_001254651.1	O76094-2
SRP72	NR_151856.2		n.39G>C		non_coding_transcript_exon	Exon 1 of 20

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SRP72	ENST00000642900.1	MANE Select	c.20G>C	p.Gly7Ala	missense	Exon 1 of 19	ENSP00000495128.1	O76094-1
SRP72	ENST00000510663.6	TSL:1	c.20G>C	p.Gly7Ala	missense	Exon 1 of 17	ENSP00000424576.1	O76094-2
SRP72	ENST00000925431.1		c.20G>C	p.Gly7Ala	missense	Exon 1 of 19	ENSP00000595490.1

Frequencies

GnomAD3 genomes

AF:

0.00729

AC:

1109

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0255

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00163

AC:

326

AN:

199632

AF XY:

0.00119

show subpopulations

Gnomad AFR exome

AF:

0.0235

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000969

Gnomad OTH exome

AF:

0.00113

GnomAD4 exome

AF:

0.000731

AC:

1030

AN:

1409246

Hom.:

Cov.:

AF XY:

0.000650

AC XY:

455

AN XY:

699876

show subpopulations

African (AFR)

AF:

0.0247

AC:

738

AN:

29894

American (AMR)

AF:

0.00209

AC:

AN:

35894

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24572

East Asian (EAS)

AF:

0.0000290

AC:

AN:

34426

South Asian (SAS)

AF:

0.000173

AC:

AN:

80770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52418

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5634

European-Non Finnish (NFE)

AF:

0.0000975

AC:

106

AN:

1087612

Other (OTH)

AF:

0.00164

AC:

AN:

58026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

101

151

202

252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00730

AC:

1111

AN:

152254

Hom.:

Cov.:

AF XY:

0.00692

AC XY:

515

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0255

AC:

1059

AN:

41550

American (AMR)

AF:

0.00209

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68018

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

112

167

223

279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000468

Hom.:

Bravo

AF:

0.00873

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0173

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00216

AC:

262

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Autosomal dominant aplasia and myelodysplasia (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.016

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0067

MetaSVM

Benign

-0.33

MutationAssessor

Benign

1.2

PhyloP100

2.2

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.59

REVEL

Benign

0.27

Sift

Benign

0.31

Sift4G

Benign

0.55

Polyphen

0.060

Vest4

0.070

MVP

0.77

MPC

0.32

ClinPred

0.048

GERP RS

4.7

PromoterAI

-0.0092

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.050

gMVP

0.27

Mutation Taster

=97/3

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over