rs1063193

Positions:

• chr12-10847181-C-A
• chr12-10847181-C-G
• chr12-10847181-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007244.3(PRR4):​c.287G>T​(p.Arg96Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R96Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 29)
• Consequence: PRR4 NM_007244.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.34

Genes affected

PRR4 (HGNC:18020): (proline rich 4) This gene encodes a member of the proline-rich protein family that lacks a conserved repetitive domain. This protein may play a role in protective functions in the eye. Alternative splicing result in multiple transcript variants. Read-through transcription also exists between this gene and the upstream PRH1 (proline-rich protein HaeIII subfamily 1) gene. [provided by RefSeq, Feb 2011]

PRH1-PRR4 (HGNC:):

PRH1 (HGNC:9366): (proline rich protein HaeIII subfamily 1) This gene encodes a member of the heterogeneous family of proline-rich salivary glycoproteins. The encoded preproprotein undergoes proteolytic processing to generate one or more mature isoforms before secretion from the parotid and submandibular/sublingual glands. Multiple distinct alleles of this locus including the parotid isoelectric-focusing variant slow (PIF-s), the parotid acidic protein (Pa), and the double band slow (Db-s) isoforms have been characterized. The reference genome encodes the Db-s allele. Certain alleles of this gene are associated with susceptibility to dental caries. This gene is located in a cluster of closely related salivary proline-rich proteins on chromosome 12. Co-transcription of this gene with adjacent genes has been observed. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048701227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRR4	NM_007244.3	c.287G>T	p.Arg96Leu	missense_variant	3/4	ENST00000228811.8	NP_009175.2
PRH1-PRR4	NR_037918.2	n.1407G>T		non_coding_transcript_exon_variant	9/10
PRR4	NM_001098538.3	c.101-46G>T		intron_variant			NP_001092008.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRR4	ENST00000228811.8	c.287G>T	p.Arg96Leu	missense_variant	3/4	1	NM_007244.3	ENSP00000228811	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 69

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.033
DANN	Benign	0.80
DEOGEN2	Benign	0.017	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.38	.;T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.0	N;.
REVEL	Benign	0.023
Sift	Benign	0.078	T;.
Sift4G	Benign	0.16	T;T
Polyphen		0.33	B;.
Vest4		0.14
MutPred		0.23		Loss of MoRF binding (P = 0.0278);.;
MVP		0.030
MPC		0.097
ClinPred		0.091	T
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.062
gMVP		0.032

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1063193; hg19: chr12-10999780;