12-120978841-G-C

Position:

• chr12-120978841-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.73G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to proline at codon 25 (p.(Ala25Pro)) of NM_000545.8. This variant is located within the DNA dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a MODY Probability Calculator score > 50% and antibody-negative; however, HNF4A was not tested (PMID:5841481). Therefore, PP4 will not be applied. This variant was identified in 2 unrelated individuals with non-autoimmune non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 15841481, 21224407). In summary, c.73G>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 9/30/21): PM1_Supporting, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386952675/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A ENST00000257555.11 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 2.77

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-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.73G>C	p.Ala25Pro	missense_variant	1/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.73G>C	p.Ala25Pro	missense_variant	1/10		NP_001293108.2
HNF1A	NM_001406915.1	c.73G>C	p.Ala25Pro	missense_variant	1/9		NP_001393844.1
HNF1A	XM_024449168.2	c.73G>C	p.Ala25Pro	missense_variant	1/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.73G>C	p.Ala25Pro	missense_variant	1/10	1	NM_000545.8	ENSP00000257555	P4
HNF1A-AS1	ENST00000619441.1	n.128+1803C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 01, 2022

The c.73G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to proline at codon 25 (p.(Ala25Pro)) of NM_000545.8. This variant is located within the DNA dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a MODY Probability Calculator score > 50% and antibody-negative; however, HNF4A was not tested (PMID: 5841481). Therefore, PP4 will not be applied. This variant was identified in 2 unrelated individuals with non-autoimmune non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 15841481, 21224407). In summary, c.73G>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 9/30/21): PM1_Supporting, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Uncertain	0.67	.;D;T;D;T;.
Eigen	Benign	0.082
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationTaster	Benign	0.52	D;D;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N;.;.;.;N;N
REVEL	Pathogenic	0.68
Sift	Benign	0.15	T;.;.;.;T;T
Sift4G	Benign	0.10	T;T;T;T;T;T
Polyphen		0.26	.;.;.;.;.;B
Vest4		0.56
MutPred		0.88		Gain of methylation at K23 (P = 0.103);Gain of methylation at K23 (P = 0.103);Gain of methylation at K23 (P = 0.103);Gain of methylation at K23 (P = 0.103);Gain of methylation at K23 (P = 0.103);Gain of methylation at K23 (P = 0.103);
MVP		0.97
MPC		0.22
ClinPred		0.57	D
GERP RS		3.4
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-121416644;