rs112061448

Variant names:

• chr7-127615029-C-A
• rs112061448
• NM_001366110.1:c.211G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-127615029-C-A
• chr7-127615029-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001366110.1(PAX4):​c.211G>T​(p.Gly71Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,614,220 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G71S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: PAX4 NM_001366110.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.75
• Publications: 2 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012901366).
• BP6: Variant 7-127615029-C-A is Benign according to our data. Variant chr7-127615029-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 549523.
• BS2: High AC in GnomAd4 at 169 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX4	NM_001366110.1	MANE Select	c.211G>T	p.Gly71Cys	missense	Exon 5 of 12	NP_001353039.1
	PAX4	NM_001366111.1		c.211G>T	p.Gly71Cys	missense	Exon 3 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.211G>T	p.Gly71Cys	missense	Exon 5 of 12	ENSP00000491782.1
	PAX4	ENST00000378740.6	TSL:1	c.211G>T	p.Gly71Cys	missense	Exon 3 of 10	ENSP00000368014.4
	PAX4	ENST00000341640.6	TSL:1	c.187G>T	p.Gly63Cys	missense	Exon 2 of 9	ENSP00000339906.2

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000282 AC: 71 AN: 251402 AF XY: 0.000191

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000112 AC: 164 AN: 1461890 Hom.: 1 Cov.: 33 AF XY: 0.0000619 AC XY: 45 AN XY: 727248

African (AFR) AF: 0.00418 AC: 140 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.000182 AC: 11 AN: 60396

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74478

African (AFR) AF: 0.00354 AC: 147 AN: 41576

American (AMR) AF: 0.00137 AC: 21 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000381 Hom.: 0

Bravo AF: 0.00123

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000329 AC: 40

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Monogenic diabetes (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	PAX4-related disorder (1)
-	1	-	Type 2 diabetes mellitus;C2677132:Maturity-onset diabetes of the young type 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	0.0056
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.013	T
MetaSVM	Pathogenic	0.85	D
PhyloP100		2.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.035	D
Polyphen		0.036	B
Vest4		0.43
MVP		0.96
MPC		0.11
ClinPred		0.038	T
GERP RS		3.8
gMVP		0.54
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs112061448; hg19: chr7-127255083;