Genetic Variant HNF1A:c.-96T>C (chr12-120978673-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2BP4_StrongBS2

The NM_000545.8(HNF1A):c.-96T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000484 in 1,032,734 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 31)

Exomes 𝑓: 0.0000048 ( 1 hom. )

Consequence

HNF1A
NM_000545.8 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0400

Publications

2 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 links:

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

HNF1A-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BS2

High AC in GnomAdExome4 at 5 AD,Unknown gene.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNF1A	NM_000545.8	MANE Select	c.-96T>C	5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_000536.6
HNF1A	NM_000545.8	MANE Select	c.-96T>C	5_prime_UTR	Exon 1 of 10	NP_000536.6
HNF1A	NM_001306179.2		c.-96T>C	5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001293108.2	F5H0K0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.-96T>C	5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000257555.5	P20823-1
HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.-96T>C	5_prime_UTR	Exon 1 of 10	ENSP00000257555.5	P20823-1
HNF1A	ENST00000538646.5	TSL:1	n.-96T>C	5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000443964.1	P20823-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000900

AC:

AN:

222286

AF XY:

0.00000806

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000203

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000484

AC:

AN:

1032734

Hom.:

Cov.:

AF XY:

0.00000752

AC XY:

AN XY:

531956

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25608

American (AMR)

AF:

0.00

AC:

AN:

43918

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23502

East Asian (EAS)

AF:

0.00

AC:

AN:

37686

South Asian (SAS)

AF:

0.00

AC:

AN:

76728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42898

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4822

European-Non Finnish (NFE)

AF:

0.00000410

AC:

AN:

731292

Other (OTH)

AF:

0.0000432

AC:

AN:

46280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.0

(source)

DANN

Benign

0.42

PhyloP100

-0.040

PromoterAI

-0.020

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over