12-120999464-G-T

Variant names:

• chr12-120999464-G-T
• rs193922586
• ENST00000544413.2:c.1626G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001306179.2(HNF1A):​c.1626G>T​(p.Glu542Asp) 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 benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E542E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNF1A NM_001306179.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07666078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.1624-19G>T		intron_variant	Intron 8 of 9	ENST00000257555.11	NP_000536.6
HNF1A	XM_024449168.2	c.1698G>T	p.Glu566Asp	missense_variant	Exon 8 of 9		XP_024304936.1
HNF1A	NM_001306179.2	c.1626G>T	p.Glu542Asp	missense_variant, splice_region_variant	Exon 9 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.1432-19G>T		intron_variant	Intron 7 of 8		NP_001393844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1624-19G>T		intron_variant	Intron 8 of 9	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 70

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	0.36
DANN	Benign	0.74
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.42	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.065	T;T
MetaSVM	Uncertain	0.40	D
PROVEAN	Benign	0.11	N;N
REVEL	Benign	0.16
Sift	Benign	0.65	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.0	.;B
Vest4		0.11
MutPred		0.12		.;Gain of phosphorylation at T539 (P = 0.1526);
MVP		0.61
ClinPred		0.048	T
GERP RS		-1.9
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs193922586; hg19: chr12-121437267;