dbSNP rs35576928: PRM1:p.Arg34Ser (chr16-11281137-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002761.3(PRM1):c.102G>T(p.Arg34Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00824 in 1,614,194 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R34K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0078 ( 16 hom., cov: 33)

Exomes 𝑓: 0.0083 ( 79 hom. )

Consequence

PRM1
NM_002761.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.445

Publications

19 publications found

Variant links:

Genes affected

PRM1 (HGNC:9447): (protamine 1) Predicted to enable DNA binding activity. Predicted to be involved in DNA packaging. Predicted to act upstream of or within nucleus organization and spermatid development. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PRM1 links:

RMI2 (HGNC:28349): (RecQ mediated genome instability 2) RMI2 is a component of the BLM (RECQL3; MIM 604610) complex, which plays a role in homologous recombination-dependent DNA repair and is essential for genome stability (Xu et al., 2008 [PubMed 18923082]).[supplied by OMIM, Nov 2008]

RMI2 links:

LOC105371082 (HGNC:):

LOC105371082 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0059812963).

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRM1	NM_002761.3 link	c.102G>T	p.Arg34Ser	missense_variant	Exon 1 of 2	ENST00000312511.4	NP_002752.1
LOC105371082	XR_933070.4 link	n.178+31359C>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PRM1	ENST00000312511.4 link	c.102G>T	p.Arg34Ser	missense_variant	Exon 1 of 2	1	NM_002761.3	ENSP00000310515.3
RMI2	ENST00000572173.1 link	c.-515-14079C>A		intron_variant	Intron 1 of 4	1		ENSP00000461206.1
RMI2	ENST00000573910.1 link	n.160+31359C>A		intron_variant	Intron 1 of 1	3
RMI2	ENST00000649869.1 link	n.152+31359C>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00777

AC:

1183

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00191

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0366

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0100

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00875

AC:

2199

AN:

251444

AF XY:

0.00873

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0339

Gnomad NFE exome

AF:

0.0118

Gnomad OTH exome

AF:

0.00749

GnomAD4 exome

AF:

0.00829

AC:

12114

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00804

AC XY:

5849

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

33480

American (AMR)

AF:

0.00141

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0343

AC:

1832

AN:

53396

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00884

AC:

9831

AN:

1112002

Other (OTH)

AF:

0.00560

AC:

338

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

732

1464

2195

2927

3659

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

344

688

1032

1376

1720

<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:

0.00777

AC:

1183

AN:

152336

Hom.:

Cov.:

AF XY:

0.00879

AC XY:

655

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00190

AC:

AN:

41584

American (AMR)

AF:

0.00124

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0366

AC:

389

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0100

AC:

682

AN:

68030

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

117

176

234

293

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:

0.00766

Hom.:

Bravo

AF:

0.00460

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00296

AC:

ESP6500EA

AF:

0.0105

AC:

ExAC

AF:

0.0101

AC:

1225

EpiCase

AF:

0.00731

EpiControl

AF:

0.00794

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

6.6

(source)

DANN

Benign

0.79

DEOGEN2

Uncertain

0.54

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.035

MetaRNN

Benign

0.0060

MetaSVM

Benign

-0.96

PhyloP100

-0.45

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-6.0

REVEL

Benign

0.041

Sift4G

Uncertain

0.0030

Polyphen

0.99

Vest4

0.48

MutPred

0.39

Gain of phosphorylation at R34 (P = 0.0024);

MPC

0.32

ClinPred

0.061

GERP RS

-1.1

PromoterAI

-0.044

Neutral

(source)

Varity_R

0.69

gMVP

0.029

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over