dbSNP rs1483425149: PRRG4:p.Cys21Arg (chr11-32830590-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024081.6(PRRG4):c.61T>C(p.Cys21Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,516 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. C21G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PRRG4
NM_024081.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.387

Publications

0 publications found

Variant links:

Genes affected

PRRG4 (HGNC:30799): (proline rich and Gla domain 4) Enables WW domain binding activity. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

PRRG4 links:

ENSG00000302822 (HGNC:):

ENSG00000302822 links:

CCDC73 (HGNC:23261): (coiled-coil domain containing 73)

CCDC73 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRG4	NM_024081.6 link	c.61T>C	p.Cys21Arg	missense_variant	Exon 2 of 6	ENST00000257836.4	NP_076986.1	Q9BZD6A0A0S2Z5N9
PRRG4	XM_006718314.4 link	c.61T>C	p.Cys21Arg	missense_variant	Exon 2 of 6		XP_006718377.1	Q9BZD6A0A0S2Z5N9
PRRG4	XM_006718313.4 link	c.61T>C	p.Cys21Arg	missense_variant	Exon 2 of 5		XP_006718376.4	A0A0S2Z5M6
CCDC73	XM_047427029.1 link	c.-922A>G		upstream_gene_variant			XP_047282985.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRRG4	ENST00000257836.4 link	c.61T>C	p.Cys21Arg	missense_variant	Exon 2 of 6	1	NM_024081.6	ENSP00000257836.3		Q9BZD6
ENSG00000302822	ENST00000789882.1 link	n.-153A>G		upstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460516

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726544

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.00

AC:

AN:

44426

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

85964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111552

Other (OTH)

AF:

0.00

AC:

AN:

60338

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.063

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.31

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.68

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

1.9

PhyloP100

0.39

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.43

Sift

Benign

0.26

Sift4G

Benign

0.33

Polyphen

0.0010

Vest4

0.52

MutPred

0.67

Gain of disorder (P = 0.0047);

MVP

0.65

MPC

0.51

ClinPred

0.39

GERP RS

2.5

Varity_R

0.46

gMVP

0.86

Mutation Taster

=74/26

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over