rs2244608

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-120979185-A-G
• chr12-120979185-A-C
• chr12-120979185-A-T

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.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 (★★). The gene HNF1A is included in the ClinGen Criteria Specification Registry.

• 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
• Publications: 73 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-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

ACMG classification

Specifications for HNF1A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -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 VariationId 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.

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+91A>G		intron	N/A	NP_000536.6
	HNF1A	NM_001306179.2		c.326+91A>G		intron	N/A	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.326+91A>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+91A>G		intron	N/A	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.326+91A>G		intron	N/A	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000535955.5	TSL:1	n.42+493A>G		intron	N/A

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

African (AFR) AF: 0.137 AC: 3306 AN: 24066

American (AMR) AF: 0.368 AC: 12982 AN: 35230

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 10850 AN: 22742

East Asian (EAS) AF: 0.461 AC: 15697 AN: 34018

South Asian (SAS) AF: 0.439 AC: 31428 AN: 71534

European-Finnish (FIN) AF: 0.392 AC: 16693 AN: 42560

Middle Eastern (MID) AF: 0.477 AC: 1661 AN: 3484

European-Non Finnish (NFE) AF: 0.326 AC: 238139 AN: 730576

Other (OTH) AF: 0.347 AC: 15779 AN: 45414

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

African (AFR) AF: 0.141 AC: 5831 AN: 41482

American (AMR) AF: 0.345 AC: 5264 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1630 AN: 3468

East Asian (EAS) AF: 0.411 AC: 2112 AN: 5136

South Asian (SAS) AF: 0.433 AC: 2085 AN: 4816

European-Finnish (FIN) AF: 0.410 AC: 4333 AN: 10576

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22517 AN: 67922

Other (OTH) AF: 0.331 AC: 699 AN: 2114

Alfa AF: 0.319 Hom.: 12802

Bravo AF: 0.282

Asia WGS AF: 0.423 AC: 1467 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Maturity-onset diabetes of the young (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.094
DANN	Benign	0.59
PhyloP100		-3.3
PromoterAI		0.026	Neutral
Mutation Taster		=8/92	disease causing

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