12-121001106-A-G

Position:

• chr12-121001106-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000545.8(HNF1A):​c.1810A>G​(p.Ser604Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.738

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11156371).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.1810A>G	p.Ser604Gly	missense_variant	10/10	ENST00000257555.11	NP_000536.6
C12orf43	NM_022895.3	c.*3047T>C		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.1810A>G	p.Ser604Gly	missense_variant	10/10	1	NM_000545.8	ENSP00000257555.5
C12orf43	ENST00000288757	c.*3047T>C		3_prime_UTR_variant	6/6	1	NM_022895.3	ENSP00000288757.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;T;.;T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.81	T;T;T;T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.62	T
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.44	N;.;.;N;N
REVEL	Benign	0.22
Sift	Benign	0.055	T;.;.;D;D
Sift4G	Benign	0.23	T;T;D;T;T
Polyphen		0.0040	.;.;.;.;B
Vest4		0.059
MutPred		0.34		.;.;.;.;Loss of phosphorylation at S611 (P = 0.0248);
MVP		0.76
MPC		0.12
ClinPred		0.18	T
GERP RS		0.82
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-121438909;