12-120993703-A-G

Position:

• chr12-120993703-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5_Supporting PP4_Moderate PP3 PM2_Supporting PM1_Supporting

This summary comes from the ClinGen Evidence Repository: The c.710A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to serine at codon 237 (p.(Asn273Ser)) 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.706, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.709A>G (p.Asn237Asp) has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). 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 response to low-dose sulfonylurea) (PP4_Moderate; internal lab contributors). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.710A>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM1_Supporting, PM2_Supporting, PP4_Moderate, PM5_Supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386965461/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 8.70

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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.
• PM5: 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.710A>G	p.Asn237Ser	missense_variant	3/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.710A>G	p.Asn237Ser	missense_variant	3/10		NP_001293108.2
HNF1A	NM_001406915.1	c.710A>G	p.Asn237Ser	missense_variant	3/9		NP_001393844.1
HNF1A	XM_024449168.2	c.710A>G	p.Asn237Ser	missense_variant	3/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.710A>G	p.Asn237Ser	missense_variant	3/10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 12, 2022

The c.710A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to serine at codon 237 (p.(Asn273Ser)) 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.706, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.709A>G (p.Asn237Asp) has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). 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 response to low-dose sulfonylurea) (PP4_Moderate; internal lab contributors). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.710A>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM1_Supporting, PM2_Supporting, PP4_Moderate, PM5_Supporting, PP3. -

HNF1A-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2023

The HNF1A c.710A>G variant is predicted to result in the amino acid substitution p.Asn237Ser. This variant has been reported in several individuals with a clinical history or diagnosis of MODY (Colclough et al 2013. PubMed ID: 23348805; Dallali et al. 2019. PubMed ID: 30656436). Alternative variants affecting the same amino acid (p.Asn237His and p.Asn237Asp) have also been reported in association with MODY (Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/). This variant is interpreted as likely pathogenic by ClinGen Monogenic Diabetes Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/1676710/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;D;D;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	0.85	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.7	D;.;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0030	D;.;D;D
Sift4G	Benign	0.073	T;T;T;T
Polyphen		0.30	.;.;.;B
Vest4		0.92
MutPred		0.56		Gain of phosphorylation at N237 (P = 0.0357);Gain of phosphorylation at N237 (P = 0.0357);Gain of phosphorylation at N237 (P = 0.0357);Gain of phosphorylation at N237 (P = 0.0357);
MVP		0.95
MPC		1.2
ClinPred		0.98	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.76		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-121431506; COSMIC: COSV57458725; COSMIC: COSV57458725;