rs1169304

Positions:

• chr12-120999418-T-C
• chr12-120999418-T-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.1623+29T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 1,613,794 control chromosomes in the GnomAD database, including 531,232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44840 hom., cov: 32)
  • Exomes 𝑓: 0.81 (486392 hom.)
• Consequence: HNF1A NM_000545.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -3.77

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.387669E-7).
• BP6: Variant 12-120999418-T-C is Benign according to our data. Variant chr12-120999418-T-C is described in ClinVar as [Benign]. Clinvar id is 135505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-120999418-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.1623+29T>C		intron_variant		ENST00000257555.11	NP_000536.6
HNF1A	XM_024449168.2	c.1652T>C	p.Leu551Ser	missense_variant	8/9		XP_024304936.1
HNF1A	NM_001306179.2	c.1623+29T>C		intron_variant			NP_001293108.2
HNF1A	NM_001406915.1	c.1431+29T>C		intron_variant			NP_001393844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1623+29T>C		intron_variant		1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes AF: 0.759 AC: 115468 AN: 152032 Hom.: 44808 Cov.: 32

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.772

Gnomad AMR AF: 0.878

Gnomad ASJ AF: 0.876

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.843

Gnomad FIN AF: 0.810

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.808

Gnomad OTH AF: 0.810

GnomAD3 exomes AF: 0.823 AC: 206387 AN: 250922 Hom.: 85692 AF XY: 0.824 AC XY: 111903 AN XY: 135758

Gnomad AFR exome AF: 0.573

Gnomad AMR exome AF: 0.921

Gnomad ASJ exome AF: 0.879

Gnomad EAS exome AF: 0.874

Gnomad SAS exome AF: 0.833

Gnomad FIN exome AF: 0.801

Gnomad NFE exome AF: 0.815

Gnomad OTH exome AF: 0.837

GnomAD4 exome AF: 0.814 AC: 1190214 AN: 1461644 Hom.: 486392 Cov.: 86 AF XY: 0.815 AC XY: 592744 AN XY: 727132

Gnomad4 AFR exome AF: 0.578

Gnomad4 AMR exome AF: 0.914

Gnomad4 ASJ exome AF: 0.879

Gnomad4 EAS exome AF: 0.892

Gnomad4 SAS exome AF: 0.833

Gnomad4 FIN exome AF: 0.808

Gnomad4 NFE exome AF: 0.812

Gnomad4 OTH exome AF: 0.814

GnomAD4 genome AF: 0.759 AC: 115548 AN: 152150 Hom.: 44840 Cov.: 32 AF XY: 0.763 AC XY: 56764 AN XY: 74372

Gnomad4 AFR AF: 0.586

Gnomad4 AMR AF: 0.878

Gnomad4 ASJ AF: 0.876

Gnomad4 EAS AF: 0.870

Gnomad4 SAS AF: 0.842

Gnomad4 FIN AF: 0.810

Gnomad4 NFE AF: 0.808

Gnomad4 OTH AF: 0.812

Alfa AF: 0.785 Hom.: 8923

Bravo AF: 0.759

TwinsUK AF: 0.813 AC: 3016

ALSPAC AF: 0.817 AC: 3148

ESP6500AA AF: 0.600 AC: 2645

ESP6500EA AF: 0.817 AC: 7030

ExAC AF: 0.814 AC: 98827

Asia WGS AF: 0.876 AC: 3048 AN: 3478

EpiCase AF: 0.814

EpiControl AF: 0.817

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Maturity onset diabetes mellitus in young Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

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. Sufficient evidence is found to confer the association of this particular variant rs1169304 with MODY3. -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.20
DANN	Benign	0.62
DEOGEN2	Benign	0.23	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0065	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	8.4e-7	T
MetaSVM	Benign	-0.98	T
PROVEAN	Benign	0.20	N
REVEL	Uncertain	0.31
Sift	Benign	0.046	D
Sift4G	Benign	0.37	T
Vest4		0.021
ClinPred		0.031	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1169304; hg19: chr12-121437221; COSMIC: COSV56567579; COSMIC: COSV56567579;