chr16-57230715-T-TA

Variant names:

• chr16-57230715-T-TA
• rs864309651
• NM_133368.3:c.1279dupA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_133368.3(RSPRY1):​c.1279dupA​(p.Thr427AsnfsTer10) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RSPRY1 NM_133368.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.95
• Publications: 0 publications found

Genes affected

RSPRY1 (HGNC:29420): (ring finger and SPRY domain containing 1) This gene encodes a glycoprotein that contains a RING-type zinc finger domain and an SPRY domain of unknown function. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Feb 2015]

RSPRY1 Gene-Disease associations (from GenCC):

• progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-57230715-T-TA is Pathogenic according to our data. Variant chr16-57230715-T-TA is described in ClinVar as Pathogenic. ClinVar VariationId is 218885.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133368.3. 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
	RSPRY1	NM_133368.3	MANE Select	c.1279dupA	p.Thr427AsnfsTer10	frameshift	Exon 12 of 15	NP_588609.1
	RSPRY1	NM_001305163.2		c.1279dupA	p.Thr427AsnfsTer10	frameshift	Exon 12 of 15	NP_001292092.1
	RSPRY1	NM_001305164.2		c.1279dupA	p.Thr427AsnfsTer10	frameshift	Exon 12 of 15	NP_001292093.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPRY1	ENST00000394420.9	TSL:1 MANE Select	c.1279dupA	p.Thr427AsnfsTer10	frameshift	Exon 12 of 15	ENSP00000377942.4
	RSPRY1	ENST00000860808.1		c.1357dupA	p.Thr453AsnfsTer10	frameshift	Exon 13 of 16	ENSP00000530867.1
	RSPRY1	ENST00000970576.1		c.1315dupA	p.Thr439AsnfsTer10	frameshift	Exon 12 of 15	ENSP00000640635.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs864309651; hg19: chr16-57264627;