chr12-120996568-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 7P and 4B. PP1_Strong PM5_Supporting BS1 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The c.1136C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to threonine at codon 379 (p.(Pro379Thr)) of NM_000545.6. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00003898, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). This variant was identified in 13 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 (PMIDs 21170474, 15657605, internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a MODY probability calculator result >50% and negative genetic testing for HNF4A (PP4; internal lab contributor). This variant segregated with diabetes, with at least 4 informative meioses in 3 families (PP1_Strong; internal lab contributors). Another missense variant, c.1136C>G p.Pro379Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Pro379Thr (PM5_Supporting). In summary, this variant 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 2.1.0, approved 8/11/2023): BS1, PP3, PP4, PP1_Strong, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831957/MONDO:0015967/017

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:5 U: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: Uncertain_significance. The variant received 3 ACMG points.

• 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.
• BS1: 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>A	p.Pro379Thr	missense	Exon 6 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.1135C>A	p.Pro379Thr	missense	Exon 6 of 10	NP_001293108.2
	HNF1A	NM_001406915.1		c.1135C>A	p.Pro379Thr	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>A	p.Pro379Thr	missense	Exon 6 of 10	ENSP00000257555.5
	HNF1A	ENST00000544413.2	TSL:1	c.1135C>A	p.Pro379Thr	missense	Exon 6 of 10	ENSP00000438804.1
	HNF1A	ENST00000538646.5	TSL:1	n.*111C>A		non_coding_transcript_exon	Exon 5 of 6	ENSP00000443964.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 250080 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461638 Hom.: 0 Cov.: 36 AF XY: 0.0000165 AC XY: 12 AN XY: 727136

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86246

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53264

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

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 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: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000251 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	-	not provided (3)
1	1	-	Maturity-onset diabetes of the young type 3 (2)
1	-	-	HNF1A-related disorder (1)
1	-	-	Maturity onset diabetes mellitus in young (1)
-	1	-	Monogenic diabetes (1)
-	1	-	Type 1 diabetes mellitus 20 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.072	T
Polyphen		1.0	D
Vest4		0.95
MutPred		0.93		Loss of catalytic residue at P378 (P = 0.0116)
MVP		0.98
MPC		0.59
ClinPred		0.94	D
GERP RS		4.6
gMVP		0.81
Mutation Taster		=0/100	disease causing

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;