16-57204801-A-T

Position:

• chr16-57204801-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_133368.3(RSPRY1):​c.143A>T​(p.Asp48Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RSPRY1 NM_133368.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.70

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPRY1	NM_133368.3	c.143A>T	p.Asp48Val	missense_variant	2/15	ENST00000394420.9	NP_588609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPRY1	ENST00000394420.9	c.143A>T	p.Asp48Val	missense_variant	2/15	1	NM_133368.3	ENSP00000377942	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2023

The c.143A>T (p.D48V) alteration is located in exon 2 (coding exon 1) of the RSPRY1 gene. This alteration results from a A to T substitution at nucleotide position 143, causing the aspartic acid (D) at amino acid position 48 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	.;.;T;.;T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	.;D;.;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.4	.;.;L;.;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.3	D;D;N;D;N;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0030	D;D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D
Polyphen		0.037	.;.;B;.;B;.
Vest4		0.41, 0.41
MutPred		0.38		Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);
MVP		0.58
MPC		1.4
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.22
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs1252892814; hg19: chr16-57238713;