7-127610853-T-C

Position:

• chr7-127610853-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BA1

The ENST00000378740.6(PAX4):​c.1046A>G​(p.Ter349TrpextTer2) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 1,536,282 control chromosomes in the GnomAD database, including 456,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42467 hom., cov: 32)
  • Exomes 𝑓: 0.77 (413618 hom.)
• Consequence: PAX4 ENST00000378740.6 stop_lost
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.00600

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM4: Stoplost variant in ENST00000378740.6 Downstream stopcodon found after 8 codons.
• BP6: Variant 7-127610853-T-C is Benign according to our data. Variant chr7-127610853-T-C is described in ClinVar as [Benign]. Clinvar id is 358791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-127610853-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX4	NM_001366110.1	c.*211A>G		3_prime_UTR_variant	12/12	ENST00000639438.3	NP_001353039.1
PAX4	NM_001366111.1	c.1046A>G	p.Ter349TrpextTer2	stop_lost	10/10		NP_001353040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX4	ENST00000378740.6	c.1046A>G	p.Ter349TrpextTer2	stop_lost	10/10	1		ENSP00000368014	P2
PAX4	ENST00000639438.3	c.*211A>G		3_prime_UTR_variant	12/12	5	NM_001366110.1	ENSP00000491782	A2
PAX4	ENST00000341640.6	c.*211A>G		3_prime_UTR_variant	9/9	1		ENSP00000339906

Frequencies

GnomAD3 genomes AF: 0.743 AC: 112892 AN: 152022 Hom.: 42440 Cov.: 32

Gnomad AFR AF: 0.713

Gnomad AMI AF: 0.797

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.884

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.741

Gnomad FIN AF: 0.719

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.783

Gnomad OTH AF: 0.744

GnomAD3 exomes AF: 0.734 AC: 101797 AN: 138708 Hom.: 38217 AF XY: 0.736 AC XY: 55398 AN XY: 75220

Gnomad AFR exome AF: 0.709

Gnomad AMR exome AF: 0.723

Gnomad ASJ exome AF: 0.874

Gnomad EAS exome AF: 0.365

Gnomad SAS exome AF: 0.742

Gnomad FIN exome AF: 0.732

Gnomad NFE exome AF: 0.787

Gnomad OTH exome AF: 0.767

GnomAD4 exome AF: 0.769 AC: 1064249 AN: 1384142 Hom.: 413618 Cov.: 36 AF XY: 0.768 AC XY: 524459 AN XY: 683108

Gnomad4 AFR exome AF: 0.705

Gnomad4 AMR exome AF: 0.732

Gnomad4 ASJ exome AF: 0.878

Gnomad4 EAS exome AF: 0.338

Gnomad4 SAS exome AF: 0.743

Gnomad4 FIN exome AF: 0.733

Gnomad4 NFE exome AF: 0.787

Gnomad4 OTH exome AF: 0.767

GnomAD4 genome AF: 0.743 AC: 112969 AN: 152140 Hom.: 42467 Cov.: 32 AF XY: 0.736 AC XY: 54772 AN XY: 74382

Gnomad4 AFR AF: 0.713

Gnomad4 AMR AF: 0.750

Gnomad4 ASJ AF: 0.884

Gnomad4 EAS AF: 0.367

Gnomad4 SAS AF: 0.740

Gnomad4 FIN AF: 0.719

Gnomad4 NFE AF: 0.783

Gnomad4 OTH AF: 0.743

Alfa AF: 0.784 Hom.: 60163

Bravo AF: 0.742

TwinsUK AF: 0.773 AC: 2866

ALSPAC AF: 0.784 AC: 3022

ExAC AF: 0.676 AC: 14835

Asia WGS AF: 0.582 AC: 2027 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	- -

Type 2 diabetes mellitus Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

PAX4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Maturity onset diabetes mellitus in young Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	11
DANN	Benign	0.65
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.00026	N
MutationTaster	Benign	1.0	P;P;P
GERP RS		1.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs712700; hg19: chr7-127250907; COSMIC: COSV58387402; COSMIC: COSV58387402;