rs137853245

Variant names:

• chr12-120994277-C-A
• rs137853245
• NM_000545.8:c.827C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-120994277-C-A
• chr12-120994277-C-G
• chr12-120994277-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP1_Strong PM1_Supporting PS3_Supporting PM5_Supporting PP4_Moderate PP3

This summary comes from the ClinGen Evidence Repository: The c.827C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to aspartic acid at codon 276 (p.(Ala276Asp)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, antibody-negative, and response to low-dose sulfonylurea (PP4_Moderate, internal lab contributors). Another missense variant, c.827C>G (p.Ala276Gly), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). Also, the variant segregated with diabetes, with four informative meioses in two families with MODY (PP1_Strong; internal lab contributors). Functional studies demonstrated abnormal nuclear localization, DNA binding less than 40% of wildtype, and normal transactivation (PS3_Supporting; PMID:12574234). This variant is absent from the gnomAD European non-Finnish population, but two copies are present in the African population; therefore PM2_Supporting cannot be applied. This variant was identified in at least 12 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID:12574234, internal lab contributors). In summary, c.827C>A 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, PP4_Moderate, PP3, PM1_Supporting, PM5_Supporting, PS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA124481/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 7.49
• Publications: 12 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 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: 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_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.827C>A	p.Ala276Asp	missense	Exon 4 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.827C>A	p.Ala276Asp	missense	Exon 4 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.827C>A	p.Ala276Asp	missense	Exon 4 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.827C>A	p.Ala276Asp	missense	Exon 4 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.827C>A	p.Ala276Asp	missense	Exon 4 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000538646.5	TSL:1	n.640C>A		non_coding_transcript_exon	Exon 3 of 6	ENSP00000443964.1	P20823-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000805 AC: 2 AN: 248546 AF XY: 0.00000743

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461078 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726786

African (AFR) AF: 0.0000598 AC: 2 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111736

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	1	-	Monogenic diabetes (2)
1	-	-	Hyperinsulinism due to HNF1A deficiency (1)
1	-	-	Maturity-onset diabetes of the young type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		7.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.73		Loss of MoRF binding (P = 0.0491)
MVP		0.99
MPC		0.67
ClinPred		0.99	D
GERP RS		4.8
gMVP		0.99
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: rs137853245; hg19: chr12-121432080; COSMIC: COSV99983202;