chr12-120982457-A-G

Variant names:

• chr12-120982457-A-G
• rs7979473
• NM_000545.8:c.326+3363A>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.326+3363A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.58 in 150,652 control chromosomes in the GnomAD database, including 25,345 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 0.58 (25345 hom., cov: 29)
• Consequence: HNF1A NM_000545.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 42 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: Genomics England PanelApp, Laboratory for Molecular Medicine
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.605 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	NM_000545.8	MANE Select	c.326+3363A>G		intron	N/A	NP_000536.6
	HNF1A	NM_001306179.2		c.326+3363A>G		intron	N/A	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.326+3363A>G		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.326+3363A>G		intron	N/A	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.326+3363A>G		intron	N/A	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000535955.5	TSL:1	n.42+3765A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.580 AC: 87308 AN: 150534 Hom.: 25301 Cov.: 29

Gnomad AFR AF: 0.565

Gnomad AMI AF: 0.621

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.596

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.610

Gnomad OTH AF: 0.566

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

GnomAD4 genome AF: 0.580 AC: 87409 AN: 150652 Hom.: 25345 Cov.: 29 AF XY: 0.573 AC XY: 42201 AN XY: 73658

African (AFR) AF: 0.566 AC: 22983 AN: 40628

American (AMR) AF: 0.565 AC: 8581 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1718 AN: 3460

East Asian (EAS) AF: 0.596 AC: 3048 AN: 5116

South Asian (SAS) AF: 0.473 AC: 2256 AN: 4770

European-Finnish (FIN) AF: 0.543 AC: 5690 AN: 10488

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.610 AC: 41279 AN: 67720

Other (OTH) AF: 0.561 AC: 1174 AN: 2092

Alfa AF: 0.589 Hom.: 38740

Bravo AF: 0.580

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.53
DANN	Benign	0.18
PhyloP100		0.0
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: rs7979473; hg19: chr12-121420260;