Genetic Variant NM_203288.2:c.410A>G (chr7-33096550-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_203288.2(RP9):c.410A>G(p.His137Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,824 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. H137L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RP9
NM_203288.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.15

Publications

0 publications found

Variant links:

Genes affected

RP9 (HGNC:10288): (RP9 pre-mRNA splicing factor) The protein encoded by this gene can be bound and phosphorylated by the protooncogene PIM1 product, a serine/threonine protein kinase . This protein localizes in nuclear speckles containing the splicing factors, and has a role in pre-mRNA splicing. CBF1-interacting protein (CIR), a corepressor of CBF1, can also bind to this protein and effects alternative splicing. Mutations in this gene result in autosomal dominant retinitis pigmentosa-9. This gene has a pseudogene (GeneID: 441212), which is located in tandem array approximately 166 kb distal to this gene. [provided by RefSeq, Sep 2009]

RP9 Gene-Disease associations (from GenCC):

retinitis pigmentosa 9
Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RP9 links:

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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
RP9	NM_203288.2 link	c.410A>G	p.His137Arg	missense_variant	Exon 5 of 6	ENST00000297157.8	NP_976033.1	Q8TA86A0A090N8Z0
RP9	XM_011515468.4 link	c.308A>G	p.His103Arg	missense_variant	Exon 5 of 6		XP_011513770.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RP9	ENST00000297157.8 link	c.410A>G	p.His137Arg	missense_variant	Exon 5 of 6	1	NM_203288.2	ENSP00000297157.3		Q8TA86

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459824

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726428

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:

33440

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110160

Other (OTH)

AF:

0.00

AC:

AN:

60298

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

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

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.066

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.34

T;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.6

L;.

PhyloP100

6.2

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.8

D;D

REVEL

Uncertain

0.33

Sift

Benign

0.31

T;T

Sift4G

Benign

0.20

T;.

Polyphen

0.063

B;.

Vest4

0.82

MutPred

0.33

Gain of disorder (P = 0.0711);.;

MVP

0.76

MPC

1.1

ClinPred

0.76

GERP RS

3.5

Varity_R

0.43

gMVP

0.078

Mutation Taster

=51/49

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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