chr12-120979185-A-G

Variant names:

• chr12-120979185-A-G
• rs2244608
• NM_000545.8:c.326+91A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000545.8(HNF1A):​c.326+91A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,161,610 control chromosomes in the GnomAD database, including 69,227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7481 hom., cov: 32)
  • Exomes 𝑓: 0.34 (61746 hom.)
• Consequence: HNF1A NM_000545.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.26

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-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-120979185-A-G is Benign according to our data. Variant chr12-120979185-A-G is described in ClinVar as [Benign]. Clinvar id is 676859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.326+91A>G		intron_variant	Intron 1 of 9	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.326+91A>G		intron_variant	Intron 1 of 9		NP_001293108.2
HNF1A	NM_001406915.1	c.326+91A>G		intron_variant	Intron 1 of 8		NP_001393844.1
HNF1A	XM_024449168.2	c.326+91A>G		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.326+91A>G		intron_variant	Intron 1 of 9	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes AF: 0.296 AC: 45010 AN: 151868 Hom.: 7481 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.325

GnomAD4 exome AF: 0.343 AC: 346535 AN: 1009624 Hom.: 61746 AF XY: 0.348 AC XY: 178460 AN XY: 513206

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.368

Gnomad4 ASJ exome AF: 0.477

Gnomad4 EAS exome AF: 0.461

Gnomad4 SAS exome AF: 0.439

Gnomad4 FIN exome AF: 0.392

Gnomad4 NFE exome AF: 0.326

Gnomad4 OTH exome AF: 0.347

GnomAD4 genome AF: 0.296 AC: 45014 AN: 151986 Hom.: 7481 Cov.: 32 AF XY: 0.306 AC XY: 22699 AN XY: 74288

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.345

Gnomad4 ASJ AF: 0.470

Gnomad4 EAS AF: 0.411

Gnomad4 SAS AF: 0.433

Gnomad4 FIN AF: 0.410

Gnomad4 NFE AF: 0.332

Gnomad4 OTH AF: 0.331

Alfa AF: 0.308 Hom.: 1020

Bravo AF: 0.282

Asia WGS AF: 0.423 AC: 1467 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Maturity onset diabetes mellitus in young Benign:1

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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs2244608 with MODY3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.094
DANN	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs2244608; hg19: chr12-121416988; COSMIC: COSV99982114;