12-120993591-C-T

Variant names:

• chr12-120993591-C-T
• rs193922598
• NM_000545.8:c.598C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP1_Strong PS4 PP4_Moderate PM2_Supporting PP3 PM5

This summary comes from the ClinGen Evidence Repository: The c.598C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 200 (p.(Arg200Trp)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.775, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.599G>A, p.(Arg200Gln), has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg200Trp has a greater Grantham distance (PM5). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative autoantibodies) (PP4_Moderate; PMID:32238361). This variant was identified in at least ten unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 17440016, 9754819, 29927023, 32238361; internal lab contributors). Lastly, this variant segregated with diabetes, with five informative meioses in five families with MODY (PP1_Strong; internal lab contributors). In summary, c.598C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PP1_Strong, PM2_Supporting, PP3, PS4, PP4_Moderate, PM5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA214311/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HNF1A NM_001306179.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 0.0640
• Publications: 13 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: Pathogenic. The variant received 14 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001306179.2. 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.598C>T	p.Arg200Trp	missense	Exon 3 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.598C>T	p.Arg200Trp	missense	Exon 3 of 10	NP_001293108.2
	HNF1A	NM_001406915.1		c.598C>T	p.Arg200Trp	missense	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.598C>T	p.Arg200Trp	missense	Exon 3 of 10	ENSP00000257555.5
	HNF1A	ENST00000544413.2	TSL:1	c.598C>T	p.Arg200Trp	missense	Exon 3 of 10	ENSP00000438804.1
	HNF1A	ENST00000540108.1	TSL:1	n.*38C>T		non_coding_transcript_exon	Exon 2 of 9	ENSP00000445445.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461866 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000436 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
2	-	-	Maturity-onset diabetes of the young type 3 (2)
1	-	-	Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma (1)
1	-	-	Maturity onset diabetes mellitus in young (1)
1	-	-	Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.23	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.90	D
PhyloP100		0.064
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		-0.34
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs193922598; hg19: chr12-121431394; COSMIC: COSV57460628;