rs1169288

Variant names:

• chr12-120978847-A-C
• rs1169288
• NM_000545.8:c.79A>C

Your query was ambiguous. Multiple possible variants found:

• chr12-120978847-A-C
• chr12-120978847-A-G
• chr12-120978847-A-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000545.8(HNF1A):​c.79A>C​(p.Ile27Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,612,800 control chromosomes in the GnomAD database, including 91,048 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I27S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.29 (7186 hom., cov: 32)
  • Exomes 𝑓: 0.33 (83862 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:16 O:3
• Conservation: PhyloP100: 3.21
• Publications: 317 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

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000545.8
• BP4: Computational evidence support a benign effect (MetaRNN=0.0011825562).
• BP6: Variant 12-120978847-A-C is Benign according to our data. Variant chr12-120978847-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 14937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.401 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.79A>C	p.Ile27Leu	missense	Exon 1 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.79A>C	p.Ile27Leu	missense	Exon 1 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.79A>C	p.Ile27Leu	missense	Exon 1 of 9	NP_001393844.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.79A>C	p.Ile27Leu	missense	Exon 1 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.79A>C	p.Ile27Leu	missense	Exon 1 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000538646.5	TSL:1	n.79A>C		non_coding_transcript_exon	Exon 1 of 6	ENSP00000443964.1	P20823-4

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43843 AN: 151834 Hom.: 7184 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.458

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.311

GnomAD2 exomes AF: 0.355 AC: 88280 AN: 248756 AF XY: 0.361

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.367

Gnomad ASJ exome AF: 0.467

Gnomad EAS exome AF: 0.415

Gnomad FIN exome AF: 0.399

Gnomad NFE exome AF: 0.337

Gnomad OTH exome AF: 0.361

GnomAD4 exome AF: 0.333 AC: 487181 AN: 1460848 Hom.: 83862 Cov.: 43 AF XY: 0.338 AC XY: 245420 AN XY: 726756

African (AFR) AF: 0.116 AC: 3874 AN: 33474

American (AMR) AF: 0.367 AC: 16383 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 12238 AN: 26120

East Asian (EAS) AF: 0.464 AC: 18405 AN: 39688

South Asian (SAS) AF: 0.421 AC: 36316 AN: 86240

European-Finnish (FIN) AF: 0.387 AC: 20456 AN: 52848

Middle Eastern (MID) AF: 0.489 AC: 2820 AN: 5766

European-Non Finnish (NFE) AF: 0.320 AC: 356084 AN: 1111646

Other (OTH) AF: 0.341 AC: 20605 AN: 60366

GnomAD4 genome AF: 0.289 AC: 43847 AN: 151952 Hom.: 7186 Cov.: 32 AF XY: 0.298 AC XY: 22137 AN XY: 74284

African (AFR) AF: 0.125 AC: 5167 AN: 41466

American (AMR) AF: 0.344 AC: 5256 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 1587 AN: 3466

East Asian (EAS) AF: 0.411 AC: 2114 AN: 5140

South Asian (SAS) AF: 0.416 AC: 2003 AN: 4816

European-Finnish (FIN) AF: 0.404 AC: 4272 AN: 10580

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.328 AC: 22266 AN: 67902

Other (OTH) AF: 0.317 AC: 668 AN: 2106

Alfa AF: 0.327 Hom.: 23881

Bravo AF: 0.274

TwinsUK AF: 0.316 AC: 1170

ALSPAC AF: 0.318 AC: 1226

ESP6500AA AF: 0.121 AC: 532

ESP6500EA AF: 0.335 AC: 2881

ExAC AF: 0.348 AC: 42182

Asia WGS AF: 0.408 AC: 1414 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	5	Maturity-onset diabetes of the young type 3 (6)
-	-	5	not specified (6)
-	-	3	not provided (3)
-	-	1	Maturity-onset diabetes of the young (1)
-	-	1	Nonpapillary renal cell carcinoma (1)
-	-	1	Type 2 diabetes mellitus (1)
-	-	-	Insulin resistance, susceptibility to (1)
-	-	-	SERUM HDL CHOLESTEROL LEVEL, MODIFIER OF (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.2	T
PhyloP100		3.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.92	N
REVEL	Uncertain	0.47
Sift	Benign	0.082	T
Sift4G	Benign	0.088	T
Polyphen		0.020	B
Vest4		0.24
MPC		0.66
ClinPred		0.020	T
GERP RS		4.5
PromoterAI		-0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.64
Mutation Taster		=95/5	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: rs1169288; hg19: chr12-121416650; COSMIC: COSV57459307;