rs587778396

chr12-120993550-T-Achr12-120993550-T-Cchr12-120993550-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000545.8(HNF1A):c.557T>A(p.Ile186Asn) 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 3 ACMG points.

• PM1: In a region_of_interest Disordered (size 22) in uniprot entity HNF1A_HUMAN there are 20 pathogenic changes around while only 3 benign (87%) in NM_000545.8
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26835728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.557T>A	p.Ile186Asn	missense_variant	3/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.557T>A	p.Ile186Asn	missense_variant	3/10
HNF1A	NM_001406915.1	c.557T>A	p.Ile186Asn	missense_variant	3/9
HNF1A	XM_024449168.2	c.557T>A	p.Ile186Asn	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.557T>A	p.Ile186Asn	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	0.17
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Benign	18
Dann	Uncertain	0.98
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.27	T;T;T;T;T;T
MetaSVM	Pathogenic	1.3	D
MutationTaster	Benign	0.94	N;N;N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.090	N;.;.;.;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.19	T;.;.;.;T;T
Sift4G	Benign	0.39	T;T;T;T;T;T
Polyphen		0.19	.;.;.;.;.;B
Vest4		0.38
MutPred		0.35		Gain of disorder (P = 0.027);Gain of disorder (P = 0.027);Gain of disorder (P = 0.027);Gain of disorder (P = 0.027);Gain of disorder (P = 0.027);Gain of disorder (P = 0.027);
MVP		0.78
MPC		1.7
ClinPred		0.24	T
GERP RS		2.5
gMVP		0.90

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-121431353;