chr7-127613497-G-C

Variant names:

• chr7-127613497-G-C
• rs3824004
• NM_001366110.1:c.598C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001366110.1(PAX4):​c.598C>G​(p.Arg200Gly) 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 pathogenic 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. R200S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAX4 NM_001366110.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.45
• Publications: 0 publications found

Genes affected

PAX4 (HGNC:8618): (paired box 4) This gene is a member of the paired box (PAX) family of transcription factors. Members of this gene family typically contain a paired box domain, an octapeptide, and a paired-type homeodomain. These genes play critical roles during fetal development and cancer growth. The paired box 4 gene is involved in pancreatic islet development and mouse studies have demonstrated a role for this gene in differentiation of insulin-producing beta cells. [provided by RefSeq, Jul 2008]

PAX4 Gene-Disease associations (from GenCC):

• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• diabetes mellitus, noninsulin-dependent

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• maturity-onset diabetes of the young type 9

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• monogenic diabetes

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366110.1. 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
	PAX4	NM_001366110.1	MANE Select	c.598C>G	p.Arg200Gly	missense	Exon 8 of 12	NP_001353039.1
	PAX4	NM_001366111.1		c.598C>G	p.Arg200Gly	missense	Exon 6 of 10	NP_001353040.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX4	ENST00000639438.3	TSL:5 MANE Select	c.598C>G	p.Arg200Gly	missense	Exon 8 of 12	ENSP00000491782.1
	PAX4	ENST00000378740.6	TSL:1	c.598C>G	p.Arg200Gly	missense	Exon 6 of 10	ENSP00000368014.4
	PAX4	ENST00000341640.6	TSL:1	c.574C>G	p.Arg192Gly	missense	Exon 5 of 9	ENSP00000339906.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		1.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.85		Loss of stability (P = 0.0104)
MVP		0.98
MPC		0.35
ClinPred		1.0	D
GERP RS		4.9
gMVP		0.88
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs3824004; hg19: chr7-127253551; COSMIC: COSV58389110;