chr12-121001053-TTGCCTCTGCAG-T

Variant names:

• chr12-121001053-TTGCCTCTGCAG-T
• NM_022895.3:c.*3089_*3099delCTGCAGAGGCA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_000545.8(HNF1A):​c.1769-9_1770delCCTCTGCAGTG​(p.Ser591fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. V590V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNF1A NM_000545.8 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 7.86
• Publications: 0 publications found

Genes affected

C12orf43 (HGNC:25719): (chromosome 12 open reading frame 43) Predicted to be involved in Spemann organizer formation and negative regulation of Wnt signaling pathway. Predicted to be located in nuclear envelope. [provided by Alliance of Genome Resources, Apr 2022]

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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
• PP5: Variant 12-121001053-TTGCCTCTGCAG-T is Pathogenic according to our data. Variant chr12-121001053-TTGCCTCTGCAG-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3370444.Status of the report is reviewed_by_expert_panel, 3 stars.

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
	C12orf43	NM_022895.3	MANE Select	c.*3089_*3099delCTGCAGAGGCA		3_prime_UTR	Exon 6 of 6	NP_075046.1
	HNF1A	NM_000545.8	MANE Select	c.1769-9_1770delCCTCTGCAGTG	p.Ser591fs	frameshift splice_acceptor splice_region intron	Exon 10 of 10	NP_000536.6
	C12orf43	NM_001286191.2		c.*3089_*3099delCTGCAGAGGCA		3_prime_UTR	Exon 6 of 6	NP_001273120.1	F5H7W8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C12orf43	ENST00000288757.7	TSL:1 MANE Select	c.*3089_*3099delCTGCAGAGGCA		3_prime_UTR	Exon 6 of 6	ENSP00000288757.5	Q96C57
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.1769-9_1770delCCTCTGCAGTG	p.Ser591fs	frameshift splice_acceptor splice_region intron	Exon 10 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.1790-9_1791delCCTCTGCAGTG	p.Ser598fs	frameshift splice_acceptor splice_region intron	Exon 10 of 10	ENSP00000438804.1	F5H0K0

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

Splicing

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

Other links and lift over

hg19: chr12-121438856;