12-120989098-G-C

Variant names:

• chr12-120989098-G-C
• rs12427353
• NM_000545.8:c.526+66G>C

Variant summary

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

The NM_000545.8(HNF1A):​c.526+66G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,479,890 control chromosomes in the GnomAD database, including 23,588 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1767 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21821 hom.)
• Consequence: HNF1A NM_000545.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0650
• Publications: 68 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=-0.74).
• BP6: Variant 12-120989098-G-C is Benign according to our data. Variant chr12-120989098-G-C is described in ClinVar as [Benign]. Clinvar id is 1253208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.526+66G>C		intron_variant	Intron 2 of 9	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.526+66G>C		intron_variant	Intron 2 of 9		NP_001293108.2
HNF1A	NM_001406915.1	c.526+66G>C		intron_variant	Intron 2 of 8		NP_001393844.1
HNF1A	XM_024449168.2	c.526+66G>C		intron_variant	Intron 2 of 8		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.526+66G>C		intron_variant	Intron 2 of 9	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19818 AN: 152084 Hom.: 1766 Cov.: 32

Gnomad AFR AF: 0.0313

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0347

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.152

GnomAD4 exome AF: 0.172 AC: 228782 AN: 1327688 Hom.: 21821 AF XY: 0.169 AC XY: 112462 AN XY: 664156

African (AFR) AF: 0.0291 AC: 897 AN: 30832

American (AMR) AF: 0.0931 AC: 3762 AN: 40396

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 5396 AN: 25032

East Asian (EAS) AF: 0.000211 AC: 8 AN: 37970

South Asian (SAS) AF: 0.0411 AC: 3331 AN: 81114

European-Finnish (FIN) AF: 0.229 AC: 11098 AN: 48444

Middle Eastern (MID) AF: 0.165 AC: 912 AN: 5540

European-Non Finnish (NFE) AF: 0.194 AC: 194112 AN: 1002404

Other (OTH) AF: 0.166 AC: 9266 AN: 55956

GnomAD4 genome AF: 0.130 AC: 19812 AN: 152202 Hom.: 1767 Cov.: 32 AF XY: 0.126 AC XY: 9407 AN XY: 74408

African (AFR) AF: 0.0312 AC: 1298 AN: 41552

American (AMR) AF: 0.115 AC: 1760 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 741 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5180

South Asian (SAS) AF: 0.0349 AC: 168 AN: 4814

European-Finnish (FIN) AF: 0.221 AC: 2348 AN: 10602

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 13015 AN: 67968

Other (OTH) AF: 0.149 AC: 316 AN: 2114

Alfa AF: 0.0926 Hom.: 134

Bravo AF: 0.121

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.84
PhyloP100		0.065
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs12427353; hg19: chr12-121426901;