NM_000545.8:c.539C>G

Variant names:

• chr12-120993532-C-G
• rs1060499866
• NM_000545.8:c.539C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP4_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.539C>G variant in the HNF1 homeobox A gene, HNF1A causes an amino acid change of alanine to glycine at codon 180 (p.(Ala180Gly)) of NM_000545.8. 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 sensitive to sulfonylurea treatment) (PP4_Moderate; internal lab contributor). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.539C>T (p.Ala180Val) has been classified as a likely benign by the ClinGen MDEP; therefore, PM5 will not be applied. This variant has a REVEL score of 0.492, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.539C>G meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/111/2023): PP4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386963548/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 5.61
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: 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.539C>G	p.Ala180Gly	missense	Exon 3 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.539C>G	p.Ala180Gly	missense	Exon 3 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.539C>G	p.Ala180Gly	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.539C>G	p.Ala180Gly	missense	Exon 3 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.539C>G	p.Ala180Gly	missense	Exon 3 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000540108.1	TSL:1	n.339C>G		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

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
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.093
Eigen_PC	Benign	0.098
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.35	T
MetaSVM	Pathogenic	1.1	D
PhyloP100		5.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.49
Sift	Benign	0.091	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.55
MutPred		0.31		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.88
MPC		1.7
ClinPred		0.97	D
GERP RS		5.0
gMVP		0.95
Mutation Taster		=33/67	disease causing

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: rs1060499866; hg19: chr12-121431335;