rs1555211927

Variant names:

• chr12-120993668-CAAG-C
• rs1555211927
• NM_000545.8:c.676_678delAAG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1_Supporting PM4_Supporting PM2_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The c.676_678del variant in the HNF1 homeobox A gene, HNF1A, is a three base pair deletion resulting in the in-frame deletion of one amino acid at codon 226 (p.(Lys226del)) within exon 3 of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). The c.676_678del variant is predicted to change the length of the protein due to an in-frame deletion of a single amino acid in a nonrepeat region (PM4_Supporting). Lastly, this variant was identified in an individual with a clinical history specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). In summary, c.676_678del 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 9/30/21): PM1_Supporting, PM2_Supporting, PM4_Supporting, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA482164157/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 conservative_inframe_deletion
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 B:1
• Conservation: PhyloP100: 8.78
• 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 Gene-Disease associations (from GenCC):

• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• type 1 diabetes mellitus 20

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young type 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hyperinsulinism due to HNF1A deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• nonpapillary renal cell carcinoma

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.676_678delAAG	p.Lys226del	conservative_inframe_deletion	Exon 3 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.676_678delAAG	p.Lys226del	conservative_inframe_deletion	Exon 3 of 10	NP_001293108.2
	HNF1A	NM_001406915.1		c.676_678delAAG	p.Lys226del	conservative_inframe_deletion	Exon 3 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.676_678delAAG	p.Lys226del	conservative_inframe_deletion	Exon 3 of 10	ENSP00000257555.5
	HNF1A	ENST00000544413.2	TSL:1	c.676_678delAAG	p.Lys226del	conservative_inframe_deletion	Exon 3 of 10	ENSP00000438804.1
	HNF1A	ENST00000540108.1	TSL:1	n.*116_*118delAAG		non_coding_transcript_exon	Exon 2 of 9	ENSP00000445445.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Maturity onset diabetes mellitus in young (1)
1	-	-	Maturity-onset diabetes of the young type 3 (1)
-	1	-	Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.8
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1555211927; hg19: chr12-121431471;