rs886039544

Variant names:

• chr12-120994229-C-A
• rs886039544
• NM_000545.8:c.779C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-120994229-C-A
• chr12-120994229-C-G
• chr12-120994229-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3 PM2_Supporting PM1_Supporting PM5_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.779C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to lysine at codon 260 (p.(Thr260Lys)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.925, which is greater than the MDEP VCEP threshold of 0.70 (PP3). 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 was identified in two 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). One of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result nearly 50%, negative genetic testing for HNF4A, and negative antibodies). While the MODY probability score was slightly below 50%, the patient was on insulin with a C-peptide in the normal range and thus the score was likely an underestimate, and clinical judgment was used to apply PP4_Moderate (internal lab contributors). Another missense variant, c.779C>T p.Thr260Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Thr260Lys (PM5_Supporting). In summary, c.779C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386966081/MONDO:0015967/085

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 7.49
• Publications: 0 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: Likely_pathogenic. The variant received 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 rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.779C>A	p.Thr260Lys	missense_variant	Exon 4 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.779C>A	p.Thr260Lys	missense_variant	Exon 4 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.779C>A	p.Thr260Lys	missense_variant	Exon 4 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.779C>A	p.Thr260Lys	missense_variant	Exon 4 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.779C>A	p.Thr260Lys	missense_variant	Exon 4 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Sep 19, 2023

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.779C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to lysine at codon 260 (p.(Thr260Lys)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.925, which is greater than the MDEP VCEP threshold of 0.70 (PP3). 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 was identified in two 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). One of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result nearly 50%, negative genetic testing for HNF4A, and negative antibodies). While the MODY probability score was slightly below 50%, the patient was on insulin with a C-peptide in the normal range and thus the score was likely an underestimate, and clinical judgment was used to apply PP4_Moderate (internal lab contributors). Another missense variant, c.779C>T p.Thr260Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Thr260Lys (PM5_Supporting). In summary, c.779C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;D;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.5	D;.;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.96
MutPred		0.82		Gain of methylation at T260 (P = 0.0167);Gain of methylation at T260 (P = 0.0167);Gain of methylation at T260 (P = 0.0167);Gain of methylation at T260 (P = 0.0167);
MVP		0.97
MPC		2.3
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.99
Mutation Taster		=4/96	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: rs886039544; hg19: chr12-121432032;