12-120978920-G-T

Variant names:

• chr12-120978920-G-T
• rs776710848
• NM_000545.8:c.152G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000545.8(HNF1A):​c.152G>T​(p.Gly51Val) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G51D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63
• Publications: 2 publications found

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]

HNF1A-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 6 uncertain in NM_000545.8
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17966405).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000545.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	NM_000545.8	MANE Select	c.152G>T	p.Gly51Val	missense	Exon 1 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.152G>T	p.Gly51Val	missense	Exon 1 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.152G>T	p.Gly51Val	missense	Exon 1 of 9	NP_001393844.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.152G>T	p.Gly51Val	missense	Exon 1 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.152G>T	p.Gly51Val	missense	Exon 1 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000538646.5	TSL:1	n.152G>T		non_coding_transcript_exon	Exon 1 of 6	ENSP00000443964.1	P20823-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.37	D
PhyloP100		1.6
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.31
Sift	Benign	0.043	D
Sift4G	Benign	0.25	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.47		Loss of relative solvent accessibility (P = 0.0404)
MVP		0.81
MPC		0.32
ClinPred		0.10	T
GERP RS		2.9
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.50
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs776710848; hg19: chr12-121416723;