12-120988897-C-T

Variant names:

• chr12-120988897-C-T
• rs137853244
• NM_000545.8:c.391C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP1_Strong PS4 PM2_Supporting PP3 PM5 PM1

This summary comes from the ClinGen Evidence Repository: The c.391C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 131 (p.(R131W)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). and is predicted to be deleterious by computational evidence, with a REVEL score of 0.903, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.392G>A (p.Arg131Gln) has been interpreted as pathogenic by the ClinGen MDEP and p.Arg131Trp has an equal or greater Grantham distance. (PM5). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 44 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:9166684, PMID:9075818, PMID:22060211, internal lab contributors). However, the MODY probability is unable to be calculated due to lack of clinical information (PMID:9166684, PMID:9075818, PMID:22060211 internal lab contributors). This variant segregated with disease with 11 informative meioses in six families with MODY (PP1_Strong, internal lab contributor). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0): PP1_Strong, PS4, PM1, PM5, PP3, PM2_Supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA124478/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 0.0380
• Publications: 30 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.
• PM1: 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.

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.391C>T	p.Arg131Trp	missense	Exon 2 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.391C>T	p.Arg131Trp	missense	Exon 2 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.391C>T	p.Arg131Trp	missense	Exon 2 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.391C>T	p.Arg131Trp	missense	Exon 2 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.391C>T	p.Arg131Trp	missense	Exon 2 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000538646.5	TSL:1	n.391C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000443964.1	P20823-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461868 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727238

African (AFR) AF: 0.0000299 AC: 1 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: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112000

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

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000259 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Maturity-onset diabetes of the young type 3 (3)
3	-	-	not provided (3)
1	-	-	Maturity-onset diabetes of the young (1)
1	-	-	Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Benign	0.17
Eigen_PC	Benign	0.086
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		0.038
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.94		Loss of disorder (P = 0.0399)
MVP		1.0
MPC		2.2
ClinPred		0.98	D
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.93
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: rs137853244; hg19: chr12-121426700; COSMIC: COSV57459367;