rs587778394

Variant names:

• chr12-120978841-G-A
• rs587778394
• NM_000545.8:c.73G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-120978841-G-A
• chr12-120978841-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.73G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to threonine at codon 25 (p.(Ala25Thr)) of transcript NM_000545.8. This variant is located within the dimerization domain (codons 1-32) 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 one individual with MODY; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold and not enough clinical information is provided to apply PP4 (PMID:35673428). In summary, c.73G>A 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 8/11/23): PM1_supporting, PM2_supporting.  LINK:https://erepo.genome.network/evrepo/ui/classification/CA160004/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HNF1A NM_001306179.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 O:2
• Conservation: PhyloP100: 2.77
• Publications: 3 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-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001306179.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	NM_000545.8	MANE Select	c.73G>A	p.Ala25Thr	missense	Exon 1 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.73G>A	p.Ala25Thr	missense	Exon 1 of 10	NP_001293108.2
	HNF1A	NM_001406915.1		c.73G>A	p.Ala25Thr	missense	Exon 1 of 9	NP_001393844.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.73G>A	p.Ala25Thr	missense	Exon 1 of 10	ENSP00000257555.5
	HNF1A	ENST00000544413.2	TSL:1	c.73G>A	p.Ala25Thr	missense	Exon 1 of 10	ENSP00000438804.1
	HNF1A	ENST00000538646.5	TSL:1	n.73G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000443964.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461076 Hom.: 0 Cov.: 46 AF XY: 0.00 AC XY: 0 AN XY: 726868

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52820

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111856

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Maturity onset diabetes mellitus in young (1)
-	1	-	Monogenic diabetes (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.24	D
PhyloP100		2.8
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.29	N
REVEL	Uncertain	0.34
Sift	Benign	0.51	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.063
MutPred		0.49		Loss of methylation at K23 (P = 0.1843)
MVP		0.69
MPC		0.16
ClinPred		0.42	T
GERP RS		3.4
PromoterAI		0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.58
Mutation Taster		=32/68	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: rs587778394; hg19: chr12-121416644;