rs201694197

chr12-120997664-C-Gchr12-120997664-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000545.8(HNF1A):c.1500C>G(p.His500Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. H500N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNF1A NM_000545.8 missense, splice_region
• Scores: Splicing: ADA: 0.0001572
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.701

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000545.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.1500C>G	p.His500Gln	missense_variant, splice_region_variant	7/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.1500C>G	p.His500Gln	missense_variant, splice_region_variant	7/10
HNF1A	XM_024449168.2	c.1500C>G	p.His500Gln	missense_variant, splice_region_variant	7/9
HNF1A	NM_001406915.1	c.1309+922C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.1500C>G	p.His500Gln	missense_variant, splice_region_variant	7/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Benign	13
Dann	Benign	0.97
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.86	D;T;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	0.90	N;N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.3	D;.;.;.;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.015	D;.;.;.;D;D
Sift4G	Benign	0.13	T;T;T;T;T;T
Polyphen		1.0	.;.;.;.;.;D
Vest4		0.84
MutPred		0.77		Loss of catalytic residue at L502 (P = 0.053);Loss of catalytic residue at L502 (P = 0.053);.;.;Loss of catalytic residue at L502 (P = 0.053);Loss of catalytic residue at L502 (P = 0.053);
MVP		0.99
MPC		0.55
ClinPred		0.92	D
GERP RS		-3.7
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.14
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-121435467;