12-10847181-C-G

Variant names:

• chr12-10847181-C-G
• rs1063193
• NM_007244.3:c.287G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007244.3(PRR4):​c.287G>C​(p.Arg96Pro) 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. 16/22 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 Benign.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRR4 NM_007244.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.34
• Publications: 35 publications found

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]

ENSG00000275778 (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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03399372).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007244.3. 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
	PRR4	NM_007244.3	MANE Select	c.287G>C	p.Arg96Pro	missense	Exon 3 of 4	NP_009175.2	Q16378-1
	PRR4	NM_001098538.3		c.101-46G>C		intron	N/A	NP_001092008.2	Q16378-2
	PRH1-PRR4	NR_037918.2		n.1407G>C		non_coding_transcript_exon	Exon 9 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRR4	ENST00000228811.8	TSL:1 MANE Select	c.287G>C	p.Arg96Pro	missense	Exon 3 of 4	ENSP00000228811.4	Q16378-1
	PRR4	ENST00000544994.5	TSL:1	c.101-46G>C		intron	N/A	ENSP00000438046.1	Q16378-2
	ENSG00000275778	ENST00000536668.2	TSL:5	n.*241G>C		non_coding_transcript_exon	Exon 9 of 10	ENSP00000482961.1	A0A087WZY1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461542 Hom.: 0 Cov.: 69 AF XY: 0.00 AC XY: 0 AN XY: 727046

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44708

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: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111788

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 66020

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.29
DANN	Benign	0.66
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.00021	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.0	N
PhyloP100		-3.3
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.67	N
REVEL	Benign	0.017
Sift	Benign	0.062	T
Sift4G	Benign	0.39	T
Polyphen		0.0010	B
Vest4		0.082
MutPred		0.22		Loss of MoRF binding (P = 0.0029)
MVP		0.030
MPC		0.16
ClinPred		0.088	T
GERP RS		-3.5
Varity_R		0.12
gMVP		0.023
Mutation Taster		=100/0	polymorphism

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: rs1063193; hg19: chr12-10999780;