NM_001366110.1:c.385C>T

Variant names:

• chr7-127614533-G-A
• rs114202595
• NM_001366110.1:c.385C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001366110.1(PAX4):​c.385C>T​(p.Arg129Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000493 in 1,594,826 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (9 hom.)
• Consequence: PAX4 NM_001366110.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:1
• Conservation: PhyloP100: 0.0830
• Publications: 40 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.096687704).
• BP6: Variant 7-127614533-G-A is Benign according to our data. Variant chr7-127614533-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13790.
• BS2: High AC in GnomAd4 at 38 Unknown,AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX4	NM_001366110.1	MANE Select	c.385C>T	p.Arg129Trp	missense	Exon 6 of 12	NP_001353039.1	A0A1W2PPX4
	PAX4	NM_001366111.1		c.385C>T	p.Arg129Trp	missense	Exon 4 of 10	NP_001353040.1	J3KPG0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX4	ENST00000639438.3	TSL:5 MANE Select	c.385C>T	p.Arg129Trp	missense	Exon 6 of 12	ENSP00000491782.1	A0A1W2PPX4
	PAX4	ENST00000378740.6	TSL:1	c.385C>T	p.Arg129Trp	missense	Exon 4 of 10	ENSP00000368014.4	J3KPG0
	PAX4	ENST00000341640.6	TSL:1	c.361C>T	p.Arg121Trp	missense	Exon 3 of 9	ENSP00000339906.2	O43316-4

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00540

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000119 AC: 26 AN: 218760 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000320

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00103

Gnomad FIN exome AF: 0.0000532

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000181

GnomAD4 exome AF: 0.000519 AC: 749 AN: 1442590 Hom.: 9 Cov.: 32 AF XY: 0.000520 AC XY: 372 AN XY: 715416

African (AFR) AF: 0.0000602 AC: 2 AN: 33220

American (AMR) AF: 0.0000237 AC: 1 AN: 42114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25682

East Asian (EAS) AF: 0.0159 AC: 620 AN: 39024

South Asian (SAS) AF: 0.00 AC: 0 AN: 82718

European-Finnish (FIN) AF: 0.0000574 AC: 3 AN: 52304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 0.0000998 AC: 110 AN: 1102258

Other (OTH) AF: 0.000218 AC: 13 AN: 59712

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74434

African (AFR) AF: 0.0000241 AC: 1 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00542 AC: 28 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000497 Hom.: 5

Bravo AF: 0.000132

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000149 AC: 18

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Maturity onset diabetes mellitus in young (1)
-	1	-	not provided (1)
-	1	-	not specified (1)
1	-	-	Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.16	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.097	T
MetaSVM	Pathogenic	0.89	D
PhyloP100		0.083
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.42
MVP		0.97
MPC		0.34
ClinPred		0.57	D
GERP RS		2.5
gMVP		0.72
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.15		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: rs114202595; hg19: chr7-127254587; COSMIC: COSV106485647;