rs751670999

Variant names:

• chr16-68352314-T-C
• rs751670999
• NM_019023.5:c.1480T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-68352314-T-C
• chr16-68352314-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_019023.5(PRMT7):​c.1480T>C​(p.Trp494Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000093 in 1,613,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: PRMT7 NM_019023.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 6.17
• Publications: 5 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 16-68352314-T-C is Pathogenic according to our data. Variant chr16-68352314-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 266021.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019023.5. 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
	PRMT7	NM_019023.5	MANE Select	c.1480T>C	p.Trp494Arg	missense	Exon 15 of 19	NP_061896.1	Q9NVM4-1
	PRMT7	NM_001351143.3		c.1480T>C	p.Trp494Arg	missense	Exon 15 of 20	NP_001338072.1	A0A8I5KYD6
	PRMT7	NM_001290018.2		c.1480T>C	p.Trp494Arg	missense	Exon 15 of 19	NP_001276947.1	Q9NVM4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRMT7	ENST00000441236.3	TSL:1 MANE Select	c.1480T>C	p.Trp494Arg	missense	Exon 15 of 19	ENSP00000409324.2	Q9NVM4-1
	PRMT7	ENST00000567542.5	TSL:1	n.1604T>C		non_coding_transcript_exon	Exon 6 of 10
	PRMT7	ENST00000897113.1		c.1480T>C	p.Trp494Arg	missense	Exon 15 of 19	ENSP00000567172.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250826 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461154 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726922

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74358

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
1	-	-	Short stature-brachydactyly-obesity-global developmental delay syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-8.9	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.78		Gain of methylation at W494 (P = 0.0633)
MVP		0.67
MPC		0.78
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.96
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs751670999; hg19: chr16-68386217;