Genetic Variant NM_000545.8:c.1768+712C>T (chr12-121000339-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000545.8(HNF1A):c.1768+712C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 156,926 control chromosomes in the GnomAD database, including 1,273 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: 𝑓 0.11 ( 1208 hom., cov: 32)

Exomes 𝑓: 0.12 ( 65 hom. )

Consequence

HNF1A
NM_000545.8 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.197

Publications

12 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:

C12orf43 (HGNC:25719): (chromosome 12 open reading frame 43) Predicted to be involved in Spemann organizer formation and negative regulation of Wnt signaling pathway. Predicted to be located in nuclear envelope. [provided by Alliance of Genome Resources, Apr 2022]

C12orf43 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8 link	c.1768+712C>T		intron_variant	Intron 9 of 9	ENST00000257555.11	NP_000536.6	P20823E0YMI7
C12orf43	NM_022895.3 link	c.*3814G>A		downstream_gene_variant		ENST00000288757.7	NP_075046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 link	c.1768+712C>T		intron_variant	Intron 9 of 9	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7
C12orf43	ENST00000288757.7 link	c.*3814G>A		downstream_gene_variant		1	NM_022895.3	ENSP00000288757.5		Q96C57

Frequencies

GnomAD3 genomes

AF:

0.110

AC:

16682

AN:

152078

Hom.:

1200

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0997

Gnomad AMI

AF:

0.111

Gnomad AMR

AF:

0.242

Gnomad ASJ

AF:

0.0965

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0613

Gnomad FIN

AF:

0.0433

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.108

Gnomad OTH

AF:

0.118

GnomAD4 exome

AF:

0.121

AC:

572

AN:

4730

Hom.:

AF XY:

0.116

AC XY:

283

AN XY:

2442

show subpopulations

African (AFR)

AF:

0.100

AC:

AN:

American (AMR)

AF:

0.262

AC:

263

AN:

1004

Ashkenazi Jewish (ASJ)

AF:

0.192

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.0447

AC:

AN:

358

European-Finnish (FIN)

AF:

0.0250

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0899

AC:

271

AN:

3016

Other (OTH)

AF:

0.0843

AC:

AN:

178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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

AF:

0.110

AC:

16715

AN:

152196

Hom.:

1208

Cov.:

AF XY:

0.108

AC XY:

8011

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0999

AC:

4148

AN:

41534

American (AMR)

AF:

0.243

AC:

3718

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0965

AC:

335

AN:

3470

East Asian (EAS)

AF:

0.00155

AC:

AN:

5174

South Asian (SAS)

AF:

0.0618

AC:

297

AN:

4806

European-Finnish (FIN)

AF:

0.0433

AC:

460

AN:

10616

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.108

AC:

7374

AN:

67998

Other (OTH)

AF:

0.116

AC:

246

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

723

1445

2168

2890

3613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

336

504

672

840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.115

Hom.:

586

Bravo

AF:

0.128

Asia WGS

AF:

0.0440

AC:

155

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.8

(source)

DANN

Benign

0.38

PhyloP100

0.20

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over