12-120978993-C-G

Variant names:

• chr12-120978993-C-G
• rs202180554
• NM_000545.8:c.225C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.225C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to glutamate at codon 75 (p.(Asp75Glu)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The nucleotide change c.225C>G, which causes the same amino acid change, was classified as a VUS by by the ClinGen MDEP; therefore, PS1 will not be applied. In summary, c.225C>G 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): PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386953857/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: -0.679
• Publications: 2 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

Specifications for HNF1A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000545.8. 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.225C>G	p.Asp75Glu	missense	Exon 1 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.225C>G	p.Asp75Glu	missense	Exon 1 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.225C>G	p.Asp75Glu	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.225C>G	p.Asp75Glu	missense	Exon 1 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.225C>G	p.Asp75Glu	missense	Exon 1 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000538646.5	TSL:1	n.225C>G		non_coding_transcript_exon	Exon 1 of 6	ENSP00000443964.1	P20823-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456572 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 724152

African (AFR) AF: 0.0000299 AC: 1 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 43642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39524

South Asian (SAS) AF: 0.00 AC: 0 AN: 85434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52902

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109754

Other (OTH) AF: 0.00 AC: 0 AN: 60202

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	14
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.19	D
PhyloP100		-0.68
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.25	N
REVEL	Uncertain	0.56
Sift	Benign	0.40	T
Sift4G	Benign	0.28	T
Polyphen		0.74	P
Vest4		0.17
MutPred		0.68		Gain of relative solvent accessibility (P = 0.2629)
MVP		0.97
MPC		0.30
ClinPred		0.39	T
GERP RS		-0.11
PromoterAI		-0.023	Neutral
gMVP		0.67
Mutation Taster		=5/95	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: rs202180554; hg19: chr12-121416796;