rs2393775

Variant names:

• chr12-120986771-G-A
• rs2393775
• NM_000545.8:c.327-2062G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-120986771-G-A
• chr12-120986771-G-C

Variant summary

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

The NM_000545.8(HNF1A):​c.327-2062G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 151,908 control chromosomes in the GnomAD database, including 28,843 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 0.61 (28843 hom., cov: 31)
• Consequence: HNF1A NM_000545.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.341
• Publications: 20 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.327-2062G>A		intron_variant	Intron 1 of 9	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.327-2062G>A		intron_variant	Intron 1 of 9		NP_001293108.2
HNF1A	NM_001406915.1	c.327-2062G>A		intron_variant	Intron 1 of 8		NP_001393844.1
HNF1A	XM_024449168.2	c.327-2062G>A		intron_variant	Intron 1 of 8		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.327-2062G>A		intron_variant	Intron 1 of 9	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes AF: 0.614 AC: 93199 AN: 151790 Hom.: 28798 Cov.: 31

Gnomad AFR AF: 0.680

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.469

Gnomad FIN AF: 0.547

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.611

Gnomad OTH AF: 0.594

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

GnomAD4 genome AF: 0.614 AC: 93301 AN: 151908 Hom.: 28843 Cov.: 31 AF XY: 0.606 AC XY: 44965 AN XY: 74238

African (AFR) AF: 0.681 AC: 28199 AN: 41428

American (AMR) AF: 0.579 AC: 8845 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1724 AN: 3470

East Asian (EAS) AF: 0.598 AC: 3090 AN: 5168

South Asian (SAS) AF: 0.470 AC: 2264 AN: 4818

European-Finnish (FIN) AF: 0.547 AC: 5755 AN: 10524

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.611 AC: 41506 AN: 67934

Other (OTH) AF: 0.589 AC: 1234 AN: 2096

Alfa AF: 0.617 Hom.: 3615

Bravo AF: 0.621

Asia WGS AF: 0.530 AC: 1846 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.8
DANN	Benign	0.57
PhyloP100		0.34
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: rs2393775; hg19: chr12-121424574; COSMIC: COSV107235414;