chr12-120988791-G-A

Variant names:

• chr12-120988791-G-A
• rs1169294
• NM_000545.8:c.327-42G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001306179.2(HNF1A):​c.327-42G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 1,595,190 control chromosomes in the GnomAD database, including 86,051 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7146 hom., cov: 33)
  • Exomes 𝑓: 0.33 (78905 hom.)
• Consequence: HNF1A NM_001306179.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.273
• Publications: 25 publications found

Genes affected

HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

HNF1A Gene-Disease associations (from GenCC):

• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• type 1 diabetes mellitus 20

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young type 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hyperinsulinism due to HNF1A deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• nonpapillary renal cell carcinoma

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-120988791-G-A is Benign according to our data. Variant chr12-120988791-G-A is described in ClinVar as Benign. ClinVar VariationId is 673535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001306179.2. 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
	HNF1A	NM_000545.8	MANE Select	c.327-42G>A		intron	N/A	NP_000536.6
	HNF1A	NM_001306179.2		c.327-42G>A		intron	N/A	NP_001293108.2
	HNF1A	NM_001406915.1		c.327-42G>A		intron	N/A	NP_001393844.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.327-42G>A		intron	N/A	ENSP00000257555.5
	HNF1A	ENST00000544413.2	TSL:1	c.327-42G>A		intron	N/A	ENSP00000438804.1
	HNF1A	ENST00000535955.5	TSL:1	n.43-8700G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44742 AN: 152044 Hom.: 7145 Cov.: 33

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.410

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.313

GnomAD2 exomes AF: 0.348 AC: 84443 AN: 242538 AF XY: 0.353

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.376

Gnomad ASJ exome AF: 0.454

Gnomad EAS exome AF: 0.406

Gnomad FIN exome AF: 0.376

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.353

GnomAD4 exome AF: 0.327 AC: 471715 AN: 1443028 Hom.: 78905 Cov.: 30 AF XY: 0.330 AC XY: 237293 AN XY: 718632

African (AFR) AF: 0.156 AC: 5171 AN: 33094

American (AMR) AF: 0.377 AC: 16554 AN: 43892

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 11895 AN: 25916

East Asian (EAS) AF: 0.452 AC: 17775 AN: 39368

South Asian (SAS) AF: 0.405 AC: 34563 AN: 85340

European-Finnish (FIN) AF: 0.367 AC: 19339 AN: 52722

Middle Eastern (MID) AF: 0.479 AC: 2750 AN: 5736

European-Non Finnish (NFE) AF: 0.313 AC: 343552 AN: 1097156

Other (OTH) AF: 0.336 AC: 20116 AN: 59804

GnomAD4 genome AF: 0.294 AC: 44744 AN: 152162 Hom.: 7146 Cov.: 33 AF XY: 0.302 AC XY: 22486 AN XY: 74382

African (AFR) AF: 0.163 AC: 6773 AN: 41528

American (AMR) AF: 0.355 AC: 5429 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1555 AN: 3472

East Asian (EAS) AF: 0.410 AC: 2118 AN: 5170

South Asian (SAS) AF: 0.399 AC: 1921 AN: 4818

European-Finnish (FIN) AF: 0.385 AC: 4072 AN: 10586

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.320 AC: 21733 AN: 67976

Other (OTH) AF: 0.319 AC: 674 AN: 2110

Alfa AF: 0.310 Hom.: 12268

Bravo AF: 0.284

Asia WGS AF: 0.399 AC: 1385 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.25
DANN	Benign	0.56
PhyloP100		-0.27
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: rs1169294; hg19: chr12-121426594; COSMIC: COSV57460094;