12-10847109-T-C

Variant names:

• chr12-10847109-T-C
• rs1047699
• NM_007244.3:c.359A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_007244.3(PRR4):​c.359A>G​(p.Gln120Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.815 in 1,609,774 control chromosomes in the GnomAD database, including 541,748 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.72 (42612 hom., cov: 31)
  • Exomes 𝑓: 0.82 (499136 hom.)
• Consequence: PRR4 NM_007244.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.61
• Publications: 30 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2321364E-6).
• BP6: Variant 12-10847109-T-C is Benign according to our data. Variant chr12-10847109-T-C is described in ClinVar as Benign. ClinVar VariationId is 3060347.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.908 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRR4	NM_007244.3	MANE Select	c.359A>G	p.Gln120Arg	missense	Exon 3 of 4	NP_009175.2
	PRR4	NM_001098538.3		c.127A>G	p.Arg43Gly	missense	Exon 3 of 4	NP_001092008.2
	PRH1-PRR4	NR_037918.2		n.1479A>G		non_coding_transcript_exon	Exon 9 of 10

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRR4	ENST00000228811.8	TSL:1 MANE Select	c.359A>G	p.Gln120Arg	missense	Exon 3 of 4	ENSP00000228811.4
	PRR4	ENST00000544994.5	TSL:1	c.127A>G	p.Arg43Gly	missense	Exon 3 of 4	ENSP00000438046.1
	ENSG00000275778	ENST00000536668.2	TSL:5	n.*313A>G		non_coding_transcript_exon	Exon 9 of 10	ENSP00000482961.1

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110161 AN: 151914 Hom.: 42604 Cov.: 31

Gnomad AFR AF: 0.428

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.830

Gnomad ASJ AF: 0.850

Gnomad EAS AF: 0.931

Gnomad SAS AF: 0.842

Gnomad FIN AF: 0.890

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.827

Gnomad OTH AF: 0.757

GnomAD2 exomes AF: 0.830 AC: 205465 AN: 247600 AF XY: 0.835

Gnomad AFR exome AF: 0.426

Gnomad AMR exome AF: 0.883

Gnomad ASJ exome AF: 0.845

Gnomad EAS exome AF: 0.933

Gnomad FIN exome AF: 0.888

Gnomad NFE exome AF: 0.833

Gnomad OTH exome AF: 0.837

GnomAD4 exome AF: 0.824 AC: 1201796 AN: 1457740 Hom.: 499136 Cov.: 63 AF XY: 0.826 AC XY: 598968 AN XY: 724946

African (AFR) AF: 0.423 AC: 14137 AN: 33452

American (AMR) AF: 0.879 AC: 39138 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.846 AC: 21981 AN: 25986

East Asian (EAS) AF: 0.945 AC: 37468 AN: 39632

South Asian (SAS) AF: 0.848 AC: 72466 AN: 85438

European-Finnish (FIN) AF: 0.887 AC: 47234 AN: 53246

Middle Eastern (MID) AF: 0.832 AC: 4779 AN: 5744

European-Non Finnish (NFE) AF: 0.825 AC: 915445 AN: 1109510

Other (OTH) AF: 0.817 AC: 49148 AN: 60184

GnomAD4 genome AF: 0.725 AC: 110183 AN: 152034 Hom.: 42612 Cov.: 31 AF XY: 0.733 AC XY: 54469 AN XY: 74322

African (AFR) AF: 0.427 AC: 17674 AN: 41410

American (AMR) AF: 0.831 AC: 12701 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.850 AC: 2951 AN: 3470

East Asian (EAS) AF: 0.930 AC: 4811 AN: 5172

South Asian (SAS) AF: 0.842 AC: 4047 AN: 4806

European-Finnish (FIN) AF: 0.890 AC: 9427 AN: 10590

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.827 AC: 56191 AN: 67980

Other (OTH) AF: 0.758 AC: 1602 AN: 2114

Alfa AF: 0.794 Hom.: 171202

Bravo AF: 0.706

TwinsUK AF: 0.818 AC: 3033

ALSPAC AF: 0.828 AC: 3193

ESP6500AA AF: 0.465 AC: 1840

ESP6500EA AF: 0.828 AC: 6918

ExAC AF: 0.821 AC: 99243

Asia WGS AF: 0.871 AC: 3029 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PRR4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.046
DANN	Benign	0.21
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0036	N
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.6
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.047
Sift	Benign	0.73	T
Sift4G	Benign	0.23	T
Polyphen		0.69	P
Vest4		0.024
MPC		0.047
ClinPred		0.011	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.070
gMVP		0.017
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1047699; hg19: chr12-10999708; COSMIC: COSV57392184; COSMIC: COSV57392184;