chr12-120978680-T-C

Variant names:

• chr12-120978680-T-C
• rs767550584
• ENST00000535955.5:n.30T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000535955.5(HNF1A):​n.30T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,281,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: HNF1A ENST00000535955.5 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.224
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000668 (101/151160) while in subpopulation AFR AF = 0.00234 (96/41046). AF 95% confidence interval is 0.00196. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 101 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.-89T>C		5_prime_UTR_variant	Exon 1 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.-89T>C		5_prime_UTR_variant	Exon 1 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.-89T>C		5_prime_UTR_variant	Exon 1 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.-89T>C		5_prime_UTR_variant	Exon 1 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.-89T>C		5_prime_UTR_variant	Exon 1 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes AF: 0.000668 AC: 101 AN: 151160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

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: 0.00

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.000111 AC: 25 AN: 225172 AF XY: 0.000104

Gnomad AFR exome AF: 0.00165

Gnomad AMR exome AF: 0.0000589

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000100

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000487 AC: 55 AN: 1130278 Hom.: 0 Cov.: 16 AF XY: 0.0000381 AC XY: 22 AN XY: 577264

African (AFR) AF: 0.00157 AC: 43 AN: 27366

American (AMR) AF: 0.0000680 AC: 3 AN: 44146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24080

East Asian (EAS) AF: 0.00 AC: 0 AN: 38188

South Asian (SAS) AF: 0.00 AC: 0 AN: 78702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5036

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 818674

Other (OTH) AF: 0.000181 AC: 9 AN: 49594

GnomAD4 genome AF: 0.000668 AC: 101 AN: 151160 Hom.: 0 Cov.: 32 AF XY: 0.000651 AC XY: 48 AN XY: 73740

African (AFR) AF: 0.00234 AC: 96 AN: 41046

American (AMR) AF: 0.000264 AC: 4 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67812

Other (OTH) AF: 0.000481 AC: 1 AN: 2078

Alfa AF: 0.000498 Hom.: 0

Bravo AF: 0.000657

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Feb 19, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 10690959, 16917892) -

HNF1A-related disorder Benign:1

Sep 08, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.9
DANN	Benign	0.39
PhyloP100		0.22
PromoterAI		0.0080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=293/7	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: rs767550584; hg19: chr12-121416483;