Genetic Variant NM_001114632.2:c.779G>C (chr15-41836857-G-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_001114632.2(JMJD7):c.779G>C(p.Arg260Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,976 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. R260H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

JMJD7
NM_001114632.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.182

Publications

0 publications found

Variant links:

Genes affected

JMJD7 (HGNC:34397): (jumonji domain containing 7) This gene encodes a highly conserved protein with a JmjC domain, which are part of the cupin metalloenzyme superfamily. JmjC proteins may function as 2-oxoglutarate-Fe(II)-dependent dioxygenases. Most tissues also express read-through transcripts from this gene into the downstream phospholipase A2, group IVB (cytosolic) gene, some of which may encode fusion proteins combining the N-terminus of this protein with the phospholipase A2, group IVB protein. [provided by RefSeq, Jul 2008]

JMJD7 links:

JMJD7-PLA2G4B (HGNC:34449): (JMJD7-PLA2G4B readthrough) This locus represents naturally-occurring readthrough transcription between the neighboring jumonji domain containing 7 (JMJD7) and phospholipase A2, group IVB (cytosolic) (PLA2G4B) genes. Readthrough transcripts encode fusion proteins that share amino acid sequence with each individual gene product, including a partial JmjC domain and downstream C2 and phospholipase A2 domains. Alternatively spliced transcript variants have been observed. [provided by RefSeq, Oct 2013]

JMJD7-PLA2G4B 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
JMJD7	NM_001114632.2 link	c.779G>C	p.Arg260Pro	missense_variant	Exon 7 of 8	ENST00000397299.9	NP_001108104.1	P0C870
JMJD7-PLA2G4B	NM_005090.4 link	c.702+306G>C		intron_variant	Intron 6 of 24		NP_005081.1	P0C869-6
JMJD7-PLA2G4B	NM_001198588.2 link	c.702+306G>C		intron_variant	Intron 6 of 23		NP_001185517.1	P0C869-7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JMJD7	ENST00000397299.9 link	c.779G>C	p.Arg260Pro	missense_variant	Exon 7 of 8	1	NM_001114632.2	ENSP00000380467.4		P0C870
JMJD7-PLA2G4B	ENST00000382448.8 link	c.702+306G>C		intron_variant	Intron 6 of 24	2		ENSP00000371886.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460976

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726780

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:

33476

American (AMR)

AF:

0.00

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52918

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111762

Other (OTH)

AF:

0.00

AC:

AN:

60362

⚠️ 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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

7.8

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.10

T;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.29

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.036

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.9

L;.

PhyloP100

-0.18

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.29

Sift

Benign

0.046

D;D

Sift4G

Benign

0.12

T;T

Polyphen

0.58

P;.

Vest4

0.66

MutPred

0.57

Loss of stability (P = 0.059);.;

MVP

0.19

MPC

0.039

ClinPred

0.17

GERP RS

-3.7

Varity_R

0.60

gMVP

0.82

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over