12-120997624-G-T

Variant names:

• chr12-120997624-G-T
• NM_000545.8:c.1460G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000545.8(HNF1A):​c.1460G>T​(p.Ser487Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. S487N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-120997624-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.1460G>T	p.Ser487Ile	missense_variant	Exon 7 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.1460G>T	p.Ser487Ile	missense_variant	Exon 7 of 10		NP_001293108.2
HNF1A	XM_024449168.2	c.1460G>T	p.Ser487Ile	missense_variant	Exon 7 of 9		XP_024304936.1
HNF1A	NM_001406915.1	c.1309+882G>T		intron_variant	Intron 6 of 8		NP_001393844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1460G>T	p.Ser487Ile	missense_variant	Exon 7 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	.;D;D;.;T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D;.;.;.;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0020	D;.;.;.;D;D
Sift4G	Benign	0.078	T;T;D;D;T;T
Polyphen		0.66	.;.;.;.;.;P
Vest4		0.69
MutPred		0.51		Loss of glycosylation at S487 (P = 0.0178);Loss of glycosylation at S487 (P = 0.0178);.;.;Loss of glycosylation at S487 (P = 0.0178);Loss of glycosylation at S487 (P = 0.0178);
MVP		0.90
MPC		0.54
ClinPred		0.96	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.86

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: chr12-121435427;