chr16-68347630-G-A

Variant names:

• chr16-68347630-G-A
• rs886039897
• NM_019023.5:c.1276-1G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_019023.5(PRMT7):​c.1276-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000267 in 1,460,998 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: not found (cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: PRMT7 NM_019023.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.69
• Publications: 1 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.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.023088023 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.4, offset of 1, new splice context is: agcgtggtgttccctctaAGtgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-68347630-G-A is Pathogenic according to our data. Variant chr16-68347630-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 266020.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRMT7	NM_019023.5	MANE Select	c.1276-1G>A		splice_acceptor intron	N/A	NP_061896.1
	PRMT7	NM_001351143.3		c.1276-1G>A		splice_acceptor intron	N/A	NP_001338072.1
	PRMT7	NM_001351144.3		c.1276-1G>A		splice_acceptor intron	N/A	NP_001338073.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRMT7	ENST00000441236.3	TSL:1 MANE Select	c.1276-1G>A		splice_acceptor intron	N/A	ENSP00000409324.2
	PRMT7	ENST00000567542.5	TSL:1	n.1537+1350G>A		intron	N/A
	PRMT7	ENST00000692632.1		c.1276-1G>A		splice_acceptor intron	N/A	ENSP00000510669.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251410 AF XY: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1460998 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 726896

African (AFR) AF: 0.0000299 AC: 1 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111256

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Short stature-brachydactyly-obesity-global developmental delay syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.7
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.65		Position offset: -37
DS_AL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs886039897; hg19: chr16-68381533;