7-127610572-C-T

Variant names:

• chr7-127610572-C-T
• rs405576
• NM_001366110.1:c.*492G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001366110.1(PAX4):​c.*492G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 275,170 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (29 hom., cov: 31)
  • Exomes 𝑓: 0.010 (17 hom.)
• Consequence: PAX4 NM_001366110.1 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.29
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 7-127610572-C-T is Benign according to our data. Variant chr7-127610572-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 358784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0328 (2493/76080) while in subpopulation SAS AF = 0.0527 (127/2410). AF 95% confidence interval is 0.0479. There are 29 homozygotes in GnomAd4. There are 1172 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2493 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.*492G>A		3_prime_UTR	Exon 12 of 12	NP_001353039.1	A0A1W2PPX4
	PAX4	NM_001366111.1		c.*280G>A		3_prime_UTR	Exon 10 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.*492G>A		3_prime_UTR	Exon 12 of 12	ENSP00000491782.1	A0A1W2PPX4
	PAX4	ENST00000341640.6	TSL:1	c.*492G>A		3_prime_UTR	Exon 9 of 9	ENSP00000339906.2	O43316-4
	PAX4	ENST00000378740.6	TSL:1	c.*280G>A		downstream_gene	N/A	ENSP00000368014.4	J3KPG0

Frequencies

GnomAD3 genomes AF: 0.0327 AC: 2487 AN: 76024 Hom.: 29 Cov.: 31

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.0864

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.0169

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.0532

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.0462

Gnomad NFE AF: 0.0304

Gnomad OTH AF: 0.0288

GnomAD4 exome AF: 0.0101 AC: 2012 AN: 199090 Hom.: 17 Cov.: 0 AF XY: 0.0106 AC XY: 1123 AN XY: 105922

African (AFR) AF: 0.0172 AC: 70 AN: 4058

American (AMR) AF: 0.00482 AC: 36 AN: 7474

Ashkenazi Jewish (ASJ) AF: 0.00682 AC: 39 AN: 5722

East Asian (EAS) AF: 0.00214 AC: 26 AN: 12178

South Asian (SAS) AF: 0.0164 AC: 467 AN: 28532

European-Finnish (FIN) AF: 0.00795 AC: 79 AN: 9938

Middle Eastern (MID) AF: 0.0151 AC: 12 AN: 796

European-Non Finnish (NFE) AF: 0.00990 AC: 1183 AN: 119490

Other (OTH) AF: 0.00917 AC: 100 AN: 10902

GnomAD4 genome AF: 0.0328 AC: 2493 AN: 76080 Hom.: 29 Cov.: 31 AF XY: 0.0316 AC XY: 1172 AN XY: 37136

African (AFR) AF: 0.0507 AC: 845 AN: 16656

American (AMR) AF: 0.0204 AC: 144 AN: 7074

Ashkenazi Jewish (ASJ) AF: 0.0169 AC: 26 AN: 1536

East Asian (EAS) AF: 0.00521 AC: 21 AN: 4032

South Asian (SAS) AF: 0.0527 AC: 127 AN: 2410

European-Finnish (FIN) AF: 0.0221 AC: 125 AN: 5654

Middle Eastern (MID) AF: 0.0431 AC: 5 AN: 116

European-Non Finnish (NFE) AF: 0.0304 AC: 1127 AN: 37092

Other (OTH) AF: 0.0303 AC: 31 AN: 1024

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.39
DANN	Benign	0.47
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs405576; hg19: chr7-127250626; COSMIC: COSV58389037; COSMIC: COSV58389037;