12-120996568-C-G

Variant names:

• chr12-120996568-C-G
• rs754729248
• NM_000545.8:c.1135C>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. BA1 PP3

This summary comes from the ClinGen Evidence Repository: The c.1135C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to alanine at codon 379 (p.(Pro379Ala)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9639, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While this variant has been identified in >20 unrelated individuals with diabetes in the literature (ClinVar ID 431970, PMID:18003757, PMID:23348805, PMID:29207974, PMID:21761282, PMID:23607861), it has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0005091, which is greater than the MDEP threshold for BA1 (greater than 0.0001) (BA1). Therefore, PS4 cannot be applied. While another variant at this codon, c.1136C>G (p.(Pro379Arg)), is classified as Pathogenic by the MDEP, the c.1135C>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): BA1, PP3. It may, however, confer an increased risk of type 2 diabetes (OR = 11.8, p = 0.0007324 at type2diabetesgenetics.org). LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831955/MONDO:0015967/017

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Benign reviewed by expert panel P:4 U:6 B:4
• Conservation: PhyloP100: 7.89
• Publications: 19 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: Benign. The variant received -7 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	NM_000545.8	MANE Select	c.1135C>G	p.Pro379Ala	missense	Exon 6 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.1135C>G	p.Pro379Ala	missense	Exon 6 of 10	NP_001293108.2
	HNF1A	NM_001406915.1		c.1135C>G	p.Pro379Ala	missense	Exon 6 of 9	NP_001393844.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.1135C>G	p.Pro379Ala	missense	Exon 6 of 10	ENSP00000257555.5
	HNF1A	ENST00000544413.2	TSL:1	c.1135C>G	p.Pro379Ala	missense	Exon 6 of 10	ENSP00000438804.1
	HNF1A	ENST00000538646.5	TSL:1	n.*111C>G		non_coding_transcript_exon	Exon 5 of 6	ENSP00000443964.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000188 AC: 47 AN: 250080 AF XY: 0.000148

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000123 AC: 180 AN: 1461638 Hom.: 1 Cov.: 36 AF XY: 0.000110 AC XY: 80 AN XY: 727136

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000850 AC: 38 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86246

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53264

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

European-Non Finnish (NFE) AF: 0.000112 AC: 125 AN: 1111954

Other (OTH) AF: 0.0000331 AC: 2 AN: 60388

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74332

African (AFR) AF: 0.0000724 AC: 3 AN: 41444

American (AMR) AF: 0.000131 AC: 2 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000251 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	3	-	Maturity-onset diabetes of the young type 3 (4)
1	2	1	not provided (4)
-	-	2	not specified (2)
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 mellitus in young (1)
-	-	1	Monogenic diabetes (1)
1	-	-	Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.93		Loss of catalytic residue at P378 (P = 0.0116)
MVP		0.98
MPC		0.56
ClinPred		0.66	D
GERP RS		4.6
gMVP		0.77
Mutation Taster		=21/79	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs754729248; hg19: chr12-121434371;