chr12-121001076-A-C

Position:

• chr12-121001076-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_000545.8(HNF1A):​c.1780A>C​(p.Ser594Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S594I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 5.82

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]

C12orf43 (HGNC:25719): (chromosome 12 open reading frame 43) Predicted to be involved in Spemann organizer formation and negative regulation of Wnt signaling pathway. Predicted to be located in nuclear envelope. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.269871).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.1780A>C	p.Ser594Arg	missense_variant	10/10	ENST00000257555.11	NP_000536.6
C12orf43	NM_022895.3	c.*3077T>G		3_prime_UTR_variant	6/6	ENST00000288757.7	NP_075046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1780A>C	p.Ser594Arg	missense_variant	10/10	1	NM_000545.8	ENSP00000257555.5
C12orf43	ENST00000288757.7	c.*3077T>G		3_prime_UTR_variant	6/6	1	NM_022895.3	ENSP00000288757.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461280 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726936

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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 18, 2022

The c.1780A>C variant in the e.g. HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to arginine at codon 594 (p.(Ser594Arg)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c. 1781G>T, p.Ser594Ile, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ser594Arg (PM5_Supporting). In summary, c.1780A>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): PM2_Supporting, PM5_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	.;D;.;T;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.86	D;D;T;D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Uncertain	0.32	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.4	N;.;.;N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D;.;.;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		0.35	.;.;.;.;B
Vest4		0.38
MutPred		0.49		.;.;.;.;Loss of phosphorylation at S601 (P = 0.017);
MVP		0.98
MPC		0.15
ClinPred		0.78	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs751112023; hg19: chr12-121438879;