NM_001366110.1:c.*493_*494insGCAC

Variant names:

• chr7-127610570-T-TGTGC
• rs375106423
• NM_001366110.1:c.*493_*494insGCAC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001366110.1(PAX4):​c.*493_*494insGCAC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (67 hom., cov: 18)
  • Exomes 𝑓: 0.0027 (1 hom.)
• Consequence: PAX4 NM_001366110.1 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.415
• 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 -10 ACMG points.

• BP6: Variant 7-127610570-T-TGTGC is Benign according to our data. Variant chr7-127610570-T-TGTGC is described in ClinVar as Likely_benign. ClinVar VariationId is 358783.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0528 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.*493_*494insGCAC		3_prime_UTR	Exon 12 of 12	NP_001353039.1	A0A1W2PPX4
	PAX4	NM_001366111.1		c.*281_*282insGCAC		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.*493_*494insGCAC		3_prime_UTR	Exon 12 of 12	ENSP00000491782.1	A0A1W2PPX4
	PAX4	ENST00000341640.6	TSL:1	c.*493_*494insGCAC		3_prime_UTR	Exon 9 of 9	ENSP00000339906.2	O43316-4
	PAX4	ENST00000378740.6	TSL:1	c.*281_*282insGCAC		downstream_gene	N/A	ENSP00000368014.4	J3KPG0

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 2600 AN: 131620 Hom.: 67 Cov.: 18

Gnomad AFR AF: 0.0548

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00859

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.0113

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.00938

Gnomad MID AF: 0.00431

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.0154

GnomAD4 exome AF: 0.00270 AC: 511 AN: 188962 Hom.: 1 Cov.: 0 AF XY: 0.00282 AC XY: 282 AN XY: 99978

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0216 AC: 118 AN: 5466

American (AMR) AF: 0.00235 AC: 18 AN: 7664

Ashkenazi Jewish (ASJ) AF: 0.00517 AC: 28 AN: 5414

East Asian (EAS) AF: 0.00584 AC: 75 AN: 12844

South Asian (SAS) AF: 0.00399 AC: 104 AN: 26080

European-Finnish (FIN) AF: 0.00246 AC: 22 AN: 8938

Middle Eastern (MID) AF: 0.00936 AC: 7 AN: 748

European-Non Finnish (NFE) AF: 0.00102 AC: 114 AN: 111460

Other (OTH) AF: 0.00242 AC: 25 AN: 10348

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0197 AC: 2598 AN: 131718 Hom.: 67 Cov.: 18 AF XY: 0.0196 AC XY: 1262 AN XY: 64296

African (AFR) AF: 0.0547 AC: 2142 AN: 39142

American (AMR) AF: 0.00858 AC: 107 AN: 12468

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 34 AN: 2578

East Asian (EAS) AF: 0.0112 AC: 56 AN: 5018

South Asian (SAS) AF: 0.00995 AC: 42 AN: 4220

European-Finnish (FIN) AF: 0.00938 AC: 83 AN: 8848

Middle Eastern (MID) AF: 0.00463 AC: 1 AN: 216

European-Non Finnish (NFE) AF: 0.00188 AC: 107 AN: 56782

Other (OTH) AF: 0.0147 AC: 26 AN: 1766

Alfa AF: 0.000930 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Maturity onset diabetes mellitus in young (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs375106423; hg19: chr7-127250624;