12-120978860-G-A

Variant names:

• chr12-120978860-G-A
• rs137853247
• NM_000545.8:c.92G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. BA1 BS3_Supporting PM1_Supporting

This summary comes from the ClinGen Evidence Repository: The c.92G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to aspartic acid at codon 31 (p.(Gly31Asp)) of NM_000545.8. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). While this variant has been noted to be a pathogenic variant in the literature, there are numerous pieces of evidence that refute this classification. Functional studies demonstrated the p.Gly31Asp protein has DNA binding above 75% of wild type, indicating that this variant does not impact protein function (PMID:32910913) (BS3_Supporting). This variant has a REVEL score of 0.591, which is between the ClinGen MDEP thresholds for PP3 and BP4, predicting neither a damaging nor benign impact on HNF1A function. This variant has a Grpmax Filtering allele frequency in gnomAD 2.1.1 of 0.000772 (0.0772%), which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). It has been was identified in >30 unrelated individuals with diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID:31365591, 31638168, 19169489, 26431509, 28395978, 20950394, 26059258, 19929997, 22432108, 27899486, 23551881, 24041679, 16917892, 21696527, and others). In summary, c.92G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): BA1, BS3_Supporting, PM1_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA124487/MONDO:0015967/017

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (3 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Benign reviewed by expert panel P:4 U:2 B:12
• Conservation: PhyloP100: 3.06
• Publications: 34 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 -8 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.92G>A	p.Gly31Asp	missense	Exon 1 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.92G>A	p.Gly31Asp	missense	Exon 1 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.92G>A	p.Gly31Asp	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.92G>A	p.Gly31Asp	missense	Exon 1 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.92G>A	p.Gly31Asp	missense	Exon 1 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000538646.5	TSL:1	n.92G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000443964.1	P20823-4

Frequencies

GnomAD3 genomes AF: 0.000782 AC: 119 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000772 AC: 192 AN: 248682 AF XY: 0.000703

Gnomad AFR exome AF: 0.000380

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000927

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.000888 AC: 1298 AN: 1461178 Hom.: 3 Cov.: 35 AF XY: 0.000860 AC XY: 625 AN XY: 726922

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.00157 AC: 70 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.000132 AC: 7 AN: 52934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00104 AC: 1161 AN: 1111858

Other (OTH) AF: 0.000861 AC: 52 AN: 60372

GnomAD4 genome AF: 0.000781 AC: 119 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000765 AC XY: 57 AN XY: 74478

African (AFR) AF: 0.000265 AC: 11 AN: 41568

American (AMR) AF: 0.00203 AC: 31 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68006

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000625 Hom.: 0

Bravo AF: 0.000861

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000692 AC: 84

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	3	not specified (4)
1	-	2	Maturity-onset diabetes of the young type 3 (3)
1	-	1	Maturity-onset diabetes of the young (2)
1	-	-	Chromophobe renal cell carcinoma (1)
1	-	-	Clear cell carcinoma of kidney (1)
-	-	1	Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma (1)
-	1	-	HNF1A-related disorder (1)
-	-	1	Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.044	T
MetaSVM	Uncertain	0.30	D
PhyloP100		3.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.55	N
REVEL	Uncertain	0.59
Sift	Benign	0.39	T
Sift4G	Benign	0.48	T
Polyphen		0.017	B
Vest4		0.57
MVP		0.98
MPC		0.66
ClinPred		0.012	T
GERP RS		3.5
PromoterAI		-0.046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
gMVP		0.83
Mutation Taster		=98/2	polymorphism

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: rs137853247; hg19: chr12-121416663;