rs151256267

Variant names:

• chr12-120994321-C-A
• rs151256267
• NM_000545.8:c.871C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-120994321-C-A
• chr12-120994321-C-G
• chr12-120994321-C-T

Variant summary

Our verdict is Uncertain significance. The variant received -2 ACMG points: 2P and 4B. BS2 PP1 PP4

This summary comes from the ClinGen Evidence Repository: The c.871C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to threonine at codon 291 (p.(Pro291Thr)) of NM_000545.8. This variant segregated with diabetes, with three informative meioses in one families with MODY (PP1; PMID:22432108). Additionally, this variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (BS2; internal lab contributor). Lastly, the c.871C>A 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) (PP4; PMID:18003757. In summary, c.871C>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): BS2, PP4, PP1 LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831857/MONDO:0015967/017

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 0.661
• Publications: 15 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 -2 ACMG points.

• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.871C>A	p.Pro291Thr	missense	Exon 4 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.871C>A	p.Pro291Thr	missense	Exon 4 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.871C>A	p.Pro291Thr	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.871C>A	p.Pro291Thr	missense	Exon 4 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.871C>A	p.Pro291Thr	missense	Exon 4 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000538646.5	TSL:1	n.684C>A		non_coding_transcript_exon	Exon 3 of 6	ENSP00000443964.1	P20823-4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000125 AC: 3 AN: 239706 AF XY: 0.0000154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000599

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000923

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000892 AC: 13 AN: 1457718 Hom.: 0 Cov.: 35 AF XY: 0.00000690 AC XY: 5 AN XY: 724894

African (AFR) AF: 0.0000598 AC: 2 AN: 33432

American (AMR) AF: 0.0000456 AC: 2 AN: 43876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 85634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1110428

Other (OTH) AF: 0.00 AC: 0 AN: 60182

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74354

African (AFR) AF: 0.0000483 AC: 2 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	3.6
DANN	Benign	0.21
DEOGEN2	Benign	0.41	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.86	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.16	T
PhyloP100		0.66
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.47	N
REVEL	Uncertain	0.59
Sift	Benign	0.60	T
Sift4G	Benign	0.52	T
Polyphen		0.014	B
Vest4		0.49
MutPred		0.65		Gain of phosphorylation at P291 (P = 0.0035)
MVP		0.96
MPC		0.13
ClinPred		0.026	T
GERP RS		1.6
gMVP		0.50
Mutation Taster		=2/98	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: rs151256267; hg19: chr12-121432124;