rs1555211448

Positions:

• chr12-120989033-G-GT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP4_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.526+2dup variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 2 of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). The computational splicing predictor SpliceAI gives a score of 0.48 for donor loss, predicting that the variant disrupts the donor site of intron 2 of HNF1A (PP3). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.526+2dup meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM2_Supporting, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA658658176/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNF1A ENST00000257555.11 splice_donor
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 7.61

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.526+2dup		splice_donor_variant		ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.526+2dup		splice_donor_variant			NP_001293108.2
HNF1A	NM_001406915.1	c.526+2dup		splice_donor_variant			NP_001393844.1
HNF1A	XM_024449168.2	c.526+2dup		splice_donor_variant			XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.526+2dup		splice_donor_variant		1	NM_000545.8	ENSP00000257555	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 05, 2017

- -

Monogenic diabetes Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 15, 2022

The c.526+2dup variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 2 of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result greater than 50%, negative genetic testing for HNF4A, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). The computational splicing predictor SpliceAI gives a score of 0.48 for donor loss, predicting that the variant disrupts the donor site of intron 2 of HNF1A (PP3). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.526+2dup meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM2_Supporting, PP4_Moderate, PP3. -

Maturity onset diabetes mellitus in young Uncertain:1

Uncertain significance, 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. However, more evidence is required to confer the association of this particular variant rs1555211448 with MODY3. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 14, 2023

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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 447494). This variant has not been reported in the literature in individuals affected with HNF1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 of the HNF1A gene. It does not directly change the encoded amino acid sequence of the HNF1A protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.64		Position offset: -33
DS_DL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555211448; hg19: chr12-121426836;