chr12-120988991-T-C

Position:

• chr12-120988991-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1_Supporting PP4_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.485T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 162 (p.(Leu162Pro)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.987, which is greater than the MDEP threshold of 0.70 (PP3). 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 persistent C-peptide) (PP4_Moderate; internal lab contributors). This variant was identified in two individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold (PMID:21224407, internal lab contributors). In summary, c.485T>C 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 September 30, 2021): PP3, PM1_Supporting, PM2_supporting, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386960483/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNF1A ENST00000257555.11 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 7.61

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.485T>C	p.Leu162Pro	missense_variant	2/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.485T>C	p.Leu162Pro	missense_variant	2/10		NP_001293108.2
HNF1A	NM_001406915.1	c.485T>C	p.Leu162Pro	missense_variant	2/9		NP_001393844.1
HNF1A	XM_024449168.2	c.485T>C	p.Leu162Pro	missense_variant	2/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.485T>C	p.Leu162Pro	missense_variant	2/10	1	NM_000545.8	ENSP00000257555	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Maturity onset diabetes mellitus in young Pathogenic:1

Likely risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs1555211434 with MODY3. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 14, 2016

- -

Monogenic diabetes Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 09, 2022

The c.485T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 162 (p.(Leu162Pro)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.987, which is greater than the MDEP threshold of 0.70 (PP3). 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 persistent C-peptide) (PP4_Moderate; internal lab contributors). This variant was identified in two individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 21224407, internal lab contributors). In summary, c.485T>C 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 September 30, 2021): PP3, PM1_Supporting, PM2_supporting, PP4_Moderate. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	.;D;D;D;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.5	D;.;.;.;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.;.;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D
Vest4		0.98
MutPred		0.87		Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);
MVP		1.0
MPC		2.7
ClinPred		1.0	D
GERP RS		4.9
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555211434; hg19: chr12-121426794;