Genetic Variant HNF1A:c.526+66G>T (chr12-120989098-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000545.8(HNF1A):c.526+66G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000452 in 1,328,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000045 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0650

Publications

68 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

monogenic diabetes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
type 1 diabetes mellitus 20
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
diabetes mellitus, noninsulin-dependent
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
maturity-onset diabetes of the young type 3
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
hyperinsulinism due to HNF1A deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
maturity-onset diabetes of the young
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
nonpapillary renal cell carcinoma
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

HNF1A links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BS2

High AC in GnomAdExome4 at 6 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8 link	c.526+66G>T	intron_variant	Intron 2 of 9	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 link	c.526+66G>T	intron_variant	Intron 2 of 9		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 link	c.526+66G>T	intron_variant	Intron 2 of 8		NP_001393844.1
HNF1A	XM_024449168.2 link	c.526+66G>T	intron_variant	Intron 2 of 8		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 link	c.526+66G>T		intron_variant	Intron 2 of 9	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000452

AC:

AN:

1328896

Hom.:

AF XY:

0.00000752

AC XY:

AN XY:

664710

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30838

American (AMR)

AF:

0.00

AC:

AN:

40402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25044

East Asian (EAS)

AF:

0.0000263

AC:

AN:

37970

South Asian (SAS)

AF:

0.00

AC:

AN:

81130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5542

European-Non Finnish (NFE)

AF:

0.00000498

AC:

AN:

1003488

Other (OTH)

AF:

0.00

AC:

AN:

55994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

134

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

0.065

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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12-120989098-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over