12-120993550-T-G

Position:

• chr12-120993550-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000545.8(HNF1A):​c.557T>G​(p.Ile186Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I186T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.41

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a mutagenesis_site No effect on transcription activation. (size 0) in uniprot entity HNF1A_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15895003).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.557T>G	p.Ile186Ser	missense_variant	3/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.557T>G	p.Ile186Ser	missense_variant	3/10
HNF1A	NM_001406915.1	c.557T>G	p.Ile186Ser	missense_variant	3/9
HNF1A	XM_024449168.2	c.557T>G	p.Ile186Ser	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.557T>G	p.Ile186Ser	missense_variant	3/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	16
DANN	Uncertain	0.97
DEOGEN2	Benign	0.22	.;T;T;T;T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.85	T;T;T;T;T;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Pathogenic	1.2	D
MutationTaster	Benign	0.93	N;N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.43	N;.;.;.;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.53	T;.;.;.;T;T
Sift4G	Benign	0.63	T;T;T;T;T;T
Polyphen		0.0010	.;.;.;.;.;B
Vest4		0.15
MutPred		0.35		Loss of catalytic residue at I186 (P = 0.0085);Loss of catalytic residue at I186 (P = 0.0085);Loss of catalytic residue at I186 (P = 0.0085);Loss of catalytic residue at I186 (P = 0.0085);Loss of catalytic residue at I186 (P = 0.0085);Loss of catalytic residue at I186 (P = 0.0085);
MVP		0.62
MPC		1.4
ClinPred		0.16	T
GERP RS		2.5
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr12-121431353;