chr12-120993663-C-T

Variant names:

• chr12-120993663-C-T
• rs193922600
• NM_000545.8:c.670C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 10 ACMG points: 10P and 0B. PP1_Strong PP4_Moderate PM2_Supporting PP3 PM1

This summary comes from the ClinGen Evidence Repository: The c.670C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to serine at codon 224 (p.(Pro224Ser)) of NM_000545.8. This variant segregated with diabetes, with four informative meioses in three families with MODY (PP1_Strong; PMID:15031772, internal lab contributors) and this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.944, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). 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 sulfonylurea sensitive) (PP4_Moderate; internal lab contributors). Additionally, 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). Lastly, the c.670C>T variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.670C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved June 4, 2021): PP1_Strong, PP3, PP4_Moderate, PM1_Supporting, PM2_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA214317/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.43
• Publications: 5 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: Likely_pathogenic. The variant received 10 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.
• 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_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.670C>T	p.Pro224Ser	missense	Exon 3 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.670C>T	p.Pro224Ser	missense	Exon 3 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.670C>T	p.Pro224Ser	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.670C>T	p.Pro224Ser	missense	Exon 3 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.670C>T	p.Pro224Ser	missense	Exon 3 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000540108.1	TSL:1	n.*110C>T		non_coding_transcript_exon	Exon 2 of 9	ENSP00000445445.1	P20823-8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.98	D
Vest4		0.75
MutPred		0.63		Gain of phosphorylation at P224 (P = 0.0396)
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		1.0
Mutation Taster		=1/99	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: rs193922600; hg19: chr12-121431466;