rs139712739

Positions:

• chr12-120993579-A-G
• chr12-120993579-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP6 BS2

The NM_000545.8(HNF1A):​c.586A>G​(p.Thr196Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000359 in 1,614,072 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T196T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 5.42

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a region_of_interest Disordered (size 22) in uniprot entity HNF1A_HUMAN there are 20 pathogenic changes around while only 3 benign (87%) in NM_000545.8
• BP6: Variant 12-120993579-A-G is Benign according to our data. Variant chr12-120993579-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435423.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=3, Benign=1}. Variant chr12-120993579-A-G is described in Lovd as [Benign]. Variant chr12-120993579-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.586A>G	p.Thr196Ala	missense_variant	3/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.586A>G	p.Thr196Ala	missense_variant	3/10
HNF1A	NM_001406915.1	c.586A>G	p.Thr196Ala	missense_variant	3/9
HNF1A	XM_024449168.2	c.586A>G	p.Thr196Ala	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.586A>G	p.Thr196Ala	missense_variant	3/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000456

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000274 AC: 69 AN: 251386 Hom.: 0 AF XY: 0.000294 AC XY: 40 AN XY: 135888

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000519

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000373 AC: 546 AN: 1461888 Hom.: 1 Cov.: 34 AF XY: 0.000366 AC XY: 266 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000449

Gnomad4 OTH exome AF: 0.000430

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000386 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000329 AC: 40

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 28, 2023	Variant summary: HNF1A c.586A>G (p.Thr196Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 251986 control chromosomes (gnomAD, Bellanne-Chantelot_2008), predominantly at a frequency of 0.00052 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.586A>G has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 3 (e.g. Bellanne-Chantelot_2008, Bowden_2008, Galan_2011). In at least one observed family, the variant did not segregate with disease: one affected sibling carried the variant and one affected sibling carried the reference allele (Galan_2011). These data do not allow any conclusion about variant significance. Experimental evidence evaluating nuclear translocation and transcription activation show the variant had no damaging effects (e.g. Galan_2011, Najmi_2017). The following publications have been ascertained in the context of this evaluation (PMID: 18003757, 18221440, 21170474, 27899486). Four ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 28, 2022

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 196 of the HNF1A protein (p.Thr196Ala). This variant is present in population databases (rs139712739, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of MODY and in unaffected individuals (PMID: 12453976, 18003757, 18221440, 21170474, 24097065, 25306193, 27899486, 30191644). ClinVar contains an entry for this variant (Variation ID: 435423). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HNF1A protein function. Experimental studies have shown that this missense change does not substantially affect HNF1A function (PMID: 21170474). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Maturity-onset diabetes of the young type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Maturity onset diabetes mellitus in young Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Uncertain	0.10
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.034
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.26	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.48	T
MutationTaster	Benign	0.96	D;D;D;D;D
Sift4G	Benign	0.35	T
Vest4		0.80
MVP		0.92
ClinPred		0.057	T
GERP RS		4.9

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: rs139712739; hg19: chr12-121431382;