16-68316074-G-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_019023.5(PRMT7):c.95G>C(p.Arg32Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,612,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

PRMT7
NM_019023.5 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.91

Publications

5 publications found

Variant links:

Genes affected

PRMT7 (HGNC:25557): (protein arginine methyltransferase 7) This gene encodes a member of the protein arginine N-methyltransferase family of proteins. The encoded enzyme transfers single methyl groups to arginine residues to generate monomethylarginines on histone proteins as well as other protein substrates. This enzyme plays a role in a wide range of biological processes, including neuronal differentiation, male germ line imprinting, small nuclear ribonucleoprotein biogenesis, and regulation of the Wnt signaling pathway. Mutations in this gene underlie multiple related syndromes in human patients characterized by intellectual disability, short stature and other features. The encoded protein may promote breast cancer cell invasion and metastasis in human patients. [provided by RefSeq, May 2017]

PRMT7 Gene-Disease associations (from GenCC):

short stature-brachydactyly-obesity-global developmental delay syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

PRMT7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 16-68316074-G-C is Pathogenic according to our data. Variant chr16-68316074-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 266022.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRMT7	NM_019023.5 link	c.95G>C	p.Arg32Thr	missense_variant, splice_region_variant	Exon 3 of 19	ENST00000441236.3	NP_061896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRMT7	ENST00000441236.3 link	c.95G>C	p.Arg32Thr	missense_variant, splice_region_variant	Exon 3 of 19	1	NM_019023.5	ENSP00000409324.2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152194

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

247148

AF XY:

0.0000225

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:

0.0000181

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1460720

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

726598

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25938

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

85954

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0000351

AC:

AN:

1111500

Other (OTH)

AF:

0.0000331

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000197

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Short stature-brachydactyly-obesity-global developmental delay syndrome

Pathogenic:2

Jul 28, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Likely pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 for a recessive condition (v4: 44 heterozygote(s), 0 homozygote(s)); This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in the literature in two families with PRMT7-related disease in a compound heterozygous state, with authors suggesting that it may induce aberrant splicing, and in an additional compound heterozygous individual in DECIPHER (PMID: 26437029); This variant has limited evidence for segregation with disease. This variant has been reported in three affected siblings (PMID: 26437029); Abnormal splicing is predicted by in silico tool and affected nucleotide is highly conserved. In silico predictions for the amino acid substitution are inconclusive and conservation is uninformative. Additional information: Variant is predicted to result in a missense amino acid change from Arg to Thr, and affects the last nucleotide of exon 3; This variant is heterozygous; This gene is associated with autosomal recessive disease; Alternative amino acid change(s) at the same position are present in gnomAD (Highest alelle count: v4: 1 heterozygote(s), 0 homozygote(s)). - No published functional evidence has been identified for this variant; No comparable missense variants have previous evidence for pathogenicity; Variant is not located in an established domain, motif, hotspot or informative constraint region; Loss of function is a known mechanism of disease in this gene and is associated with short stature, brachydactyly, intellectual developmental disability, and seizures (MIM#617157); Inheritance information for this variant is not currently available in this individual.

Jul 03, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0

.;.;.;.;.;T;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D;D;D;D;.;D

M_CAP

Uncertain

0.098

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.0023

MutationAssessor

Benign

0.0

.;.;.;.;M;M;M

PhyloP100

9.9

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.4

D;D;D;D;D;D;D

REVEL

Benign

0.0

Sift

Benign

0.22

T;D;D;D;D;D;D

Sift4G

Benign

0.27

T;D;T;T;D;D;D

Vest4

0.0

ClinPred

0.94

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.56

gMVP

0.86

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.38

Position offset: 7

DS_DL_spliceai

0.99

Position offset: 0

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over