NM_022895.3:c.*3089C>T

Variant names:

• chr12-121001064-G-A
• rs2135854372
• NM_022895.3:c.*3089C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Strong PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1769-1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice acceptor site in intron 10 of NM_000545.8. This variant, located in the donor site of exon 10 of 10, is predicted to disrupt a significant part of the transactivation domain, a functionally important region of the protein. Even though this truncated transcript is predicted to escape nonsense mediated decay in a gene in which loss-of-function is an established mechanism of disease, there is clinical evidence that variants in this region lead to a monogenic diabetes phenotype. (PVS1_Strong; PMID:23348805). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes and negative testing for HNF4A; however, the calculated MODY probability is <50% (internal lab contributors). Therefore, PP4 could not be applied. This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.1769-1G>A 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): PVS1_Strong, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386940950/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 33)
• Consequence: C12orf43 NM_022895.3 3_prime_UTR
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance reviewed by expert panel U: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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022895.3. 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.*3089C>T		3_prime_UTR	Exon 6 of 6	NP_075046.1
	HNF1A	NM_000545.8	MANE Select	c.1769-1G>A		splice_acceptor intron	N/A	NP_000536.6
	C12orf43	NM_001286191.2		c.*3089C>T		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.*3089C>T		3_prime_UTR	Exon 6 of 6	ENSP00000288757.5	Q96C57
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.1769-1G>A		splice_acceptor intron	N/A	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.1790-1G>A		splice_acceptor intron	N/A	ENSP00000438804.1	F5H0K0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.9
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.78		Position offset: 11
DS_AL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs2135854372; hg19: chr12-121438867;