chr7-127613775-T-C

Variant names:

• chr7-127613775-T-C
• rs327517
• NM_001366110.1:c.543A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001366110.1(PAX4):​c.543A>G​(p.Gln181Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,613,910 control chromosomes in the GnomAD database, including 1,216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (624 hom., cov: 31)
  • Exomes 𝑓: 0.0079 (592 hom.)
• Consequence: PAX4 NM_001366110.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.760
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 7-127613775-T-C is Benign according to our data. Variant chr7-127613775-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.76 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

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.543A>G	p.Gln181Gln	synonymous	Exon 7 of 12	NP_001353039.1
	PAX4	NM_001366111.1		c.543A>G	p.Gln181Gln	synonymous	Exon 5 of 10	NP_001353040.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX4	ENST00000639438.3	TSL:5 MANE Select	c.543A>G	p.Gln181Gln	synonymous	Exon 7 of 12	ENSP00000491782.1
	PAX4	ENST00000378740.6	TSL:1	c.543A>G	p.Gln181Gln	synonymous	Exon 5 of 10	ENSP00000368014.4
	PAX4	ENST00000341640.6	TSL:1	c.519A>G	p.Gln173Gln	synonymous	Exon 4 of 9	ENSP00000339906.2

Frequencies

GnomAD3 genomes AF: 0.0529 AC: 8041 AN: 151940 Hom.: 619 Cov.: 31

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0450

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0412

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.0426

GnomAD2 exomes AF: 0.0218 AC: 5491 AN: 251454 AF XY: 0.0167

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.0464

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0368

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00151

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.00785 AC: 11478 AN: 1461852 Hom.: 592 Cov.: 33 AF XY: 0.00692 AC XY: 5034 AN XY: 727226

African (AFR) AF: 0.168 AC: 5613 AN: 33480

American (AMR) AF: 0.0456 AC: 2040 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0401 AC: 1593 AN: 39700

South Asian (SAS) AF: 0.00393 AC: 339 AN: 86256

European-Finnish (FIN) AF: 0.000936 AC: 50 AN: 53420

Middle Eastern (MID) AF: 0.0137 AC: 79 AN: 5752

European-Non Finnish (NFE) AF: 0.000720 AC: 801 AN: 1111994

Other (OTH) AF: 0.0159 AC: 963 AN: 60392

GnomAD4 genome AF: 0.0530 AC: 8058 AN: 152058 Hom.: 624 Cov.: 31 AF XY: 0.0515 AC XY: 3830 AN XY: 74340

African (AFR) AF: 0.167 AC: 6941 AN: 41444

American (AMR) AF: 0.0448 AC: 685 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0411 AC: 212 AN: 5152

South Asian (SAS) AF: 0.00561 AC: 27 AN: 4814

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10600

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00141 AC: 96 AN: 67990

Other (OTH) AF: 0.0422 AC: 89 AN: 2110

Alfa AF: 0.0304 Hom.: 645

Bravo AF: 0.0624

Asia WGS AF: 0.0310 AC: 108 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00190

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Maturity onset diabetes mellitus in young (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.1
DANN	Benign	0.61
PhyloP100		0.76
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs327517; hg19: chr7-127253829; COSMIC: COSV58387843;