Genetic Variant NM_002761.3:c.16T>C (chr16-11281223-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_002761.3(PRM1):c.16T>C(p.Cys6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. C6S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PRM1
NM_002761.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.986

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a disulfide_bond Interchain (size 0) in uniprot entity HSP1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4138876).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002761.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRM1	NM_002761.3	MANE Select	c.16T>C	p.Cys6Arg	missense	Exon 1 of 2	NP_002752.1	P04553

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRM1	ENST00000312511.4	TSL:1 MANE Select	c.16T>C	p.Cys6Arg	missense	Exon 1 of 2	ENSP00000310515.3	P04553
RMI2	ENST00000572173.1	TSL:1	c.-515-13993A>G		intron	N/A	ENSP00000461206.1	Q96E14-2
RMI2	ENST00000573910.1	TSL:3	n.160+31445A>G		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251298

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461758

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53302

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.64

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.082

FATHMM_MKL

Benign

0.17

M_CAP

Benign

0.077

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.87

PhyloP100

0.99

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-12

REVEL

Benign

0.11

Sift4G

Benign

0.29

Polyphen

0.065

Vest4

0.63

MutPred

0.44

Gain of solvent accessibility (P = 0.0171)

MVP

0.36

MPC

1.3

ClinPred

0.98

GERP RS

3.2

PromoterAI

0.0010

Neutral

(source)

Varity_R

0.90

gMVP

0.0049

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over