12-120985583-A-G

Variant names:

• chr12-120985583-A-G
• rs11065385
• NM_000545.8:c.327-3250A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000545.8(HNF1A):​c.327-3250A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.717 in 151,470 control chromosomes in the GnomAD database, including 39,716 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.72 (39716 hom., cov: 30)
• Consequence: HNF1A NM_000545.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0860
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.865 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000545.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	NM_000545.8	MANE Select	c.327-3250A>G		intron	N/A	NP_000536.6
	HNF1A	NM_001306179.2		c.327-3250A>G		intron	N/A	NP_001293108.2
	HNF1A	NM_001406915.1		c.327-3250A>G		intron	N/A	NP_001393844.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.327-3250A>G		intron	N/A	ENSP00000257555.5
	HNF1A	ENST00000544413.2	TSL:1	c.327-3250A>G		intron	N/A	ENSP00000438804.1
	HNF1A	ENST00000535955.5	TSL:1	n.42+6891A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.717 AC: 108551 AN: 151352 Hom.: 39660 Cov.: 30

Gnomad AFR AF: 0.872

Gnomad AMI AF: 0.640

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.603

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.614

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.680

Gnomad OTH AF: 0.695

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.717 AC: 108665 AN: 151470 Hom.: 39716 Cov.: 30 AF XY: 0.708 AC XY: 52396 AN XY: 73982

African (AFR) AF: 0.872 AC: 36064 AN: 41350

American (AMR) AF: 0.658 AC: 10024 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 1915 AN: 3472

East Asian (EAS) AF: 0.603 AC: 3065 AN: 5080

South Asian (SAS) AF: 0.601 AC: 2879 AN: 4792

European-Finnish (FIN) AF: 0.614 AC: 6426 AN: 10468

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.680 AC: 46125 AN: 67786

Other (OTH) AF: 0.689 AC: 1444 AN: 2096

Alfa AF: 0.710 Hom.: 5057

Bravo AF: 0.730

Asia WGS AF: 0.606 AC: 2109 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.5
DANN	Benign	0.59
PhyloP100		-0.086
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: rs11065385; hg19: chr12-121423386;