chr12-120988742-G-A

Variant names:

• chr12-120988742-G-A
• rs1169293
• NM_000545.8:c.327-91G>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.327-91G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.92 in 1,153,512 control chromosomes in the GnomAD database, including 489,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (61428 hom., cov: 33)
  • Exomes 𝑓: 0.92 (427939 hom.)
• Consequence: HNF1A NM_001306179.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.297
• Publications: 16 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=-0.82).
• BP6: Variant 12-120988742-G-A is Benign according to our data. Variant chr12-120988742-G-A is described in ClinVar as Benign. ClinVar VariationId is 1232183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 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.327-91G>A		intron	N/A	NP_000536.6
	HNF1A	NM_001306179.2		c.327-91G>A		intron	N/A	NP_001293108.2
	HNF1A	NM_001406915.1		c.327-91G>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.327-91G>A		intron	N/A	ENSP00000257555.5
	HNF1A	ENST00000544413.2	TSL:1	c.327-91G>A		intron	N/A	ENSP00000438804.1
	HNF1A	ENST00000535955.5	TSL:1	n.43-8749G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.897 AC: 136383 AN: 152084 Hom.: 61375 Cov.: 33

Gnomad AFR AF: 0.812

Gnomad AMI AF: 0.978

Gnomad AMR AF: 0.919

Gnomad ASJ AF: 0.943

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.869

Gnomad FIN AF: 0.931

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.928

Gnomad OTH AF: 0.894

GnomAD4 exome AF: 0.924 AC: 925122 AN: 1001310 Hom.: 427939 AF XY: 0.922 AC XY: 472522 AN XY: 512504

African (AFR) AF: 0.805 AC: 19580 AN: 24312

American (AMR) AF: 0.947 AC: 35108 AN: 37088

Ashkenazi Jewish (ASJ) AF: 0.946 AC: 21570 AN: 22804

East Asian (EAS) AF: 0.998 AC: 34990 AN: 35074

South Asian (SAS) AF: 0.875 AC: 63491 AN: 72560

European-Finnish (FIN) AF: 0.935 AC: 41869 AN: 44764

Middle Eastern (MID) AF: 0.909 AC: 4068 AN: 4476

European-Non Finnish (NFE) AF: 0.927 AC: 662712 AN: 714992

Other (OTH) AF: 0.923 AC: 41734 AN: 45240

GnomAD4 genome AF: 0.897 AC: 136496 AN: 152202 Hom.: 61428 Cov.: 33 AF XY: 0.898 AC XY: 66800 AN XY: 74414

African (AFR) AF: 0.813 AC: 33718 AN: 41492

American (AMR) AF: 0.920 AC: 14070 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.943 AC: 3271 AN: 3470

East Asian (EAS) AF: 0.997 AC: 5165 AN: 5182

South Asian (SAS) AF: 0.870 AC: 4204 AN: 4834

European-Finnish (FIN) AF: 0.931 AC: 9876 AN: 10606

Middle Eastern (MID) AF: 0.925 AC: 272 AN: 294

European-Non Finnish (NFE) AF: 0.928 AC: 63141 AN: 68006

Other (OTH) AF: 0.895 AC: 1889 AN: 2110

Alfa AF: 0.914 Hom.: 159447

Bravo AF: 0.892

Asia WGS AF: 0.922 AC: 3207 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.6
DANN	Benign	0.69
PhyloP100		-0.30
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: rs1169293; hg19: chr12-121426545;