Genetic Variant NM_000545.8:c.1722C>A (chr12-120999581-C-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000545.8(HNF1A):c.1722C>A(p.Ser574Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,612,424 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S574D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00093 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications B:5O:1

Conservation

PhyloP100: 1.41

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011299312).

BP6

Variant 12-120999581-C-A is Benign according to our data. Variant chr12-120999581-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 393435.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000925 (141/152354) while in subpopulation AFR AF = 0.00329 (137/41590). AF 95% confidence interval is 0.00284. There are 1 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 141 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	HGVSp	Effect	Exon Rank	Protein	UniProt
HNF1A	NM_000545.8	MANE Select	c.1722C>A	p.Ser574Arg	missense	Exon 9 of 10	NP_000536.6
HNF1A	NM_001306179.2		c.1743C>A	p.Ser581Arg	missense	Exon 9 of 10	NP_001293108.2	F5H0K0
HNF1A	NM_001406915.1		c.1530C>A	p.Ser510Arg	missense	Exon 8 of 9	NP_001393844.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.1722C>A	p.Ser574Arg	missense	Exon 9 of 10	ENSP00000257555.5	P20823-1
HNF1A	ENST00000544413.2	TSL:1	c.1743C>A	p.Ser581Arg	missense	Exon 9 of 10	ENSP00000438804.1	F5H0K0
HNF1A	ENST00000540108.1	TSL:1	n.*1162C>A		non_coding_transcript_exon	Exon 8 of 9	ENSP00000445445.1	P20823-8

Frequencies

GnomAD3 genomes

AF:

0.000926

AC:

141

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00330

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000243

AC:

AN:

242772

AF XY:

0.000121

show subpopulations

Gnomad AFR exome

AF:

0.00352

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000103

AC:

150

AN:

1460070

Hom.:

Cov.:

AF XY:

0.0000771

AC XY:

AN XY:

726378

show subpopulations

African (AFR)

AF:

0.00406

AC:

136

AN:

33470

American (AMR)

AF:

0.000134

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111680

Other (OTH)

AF:

0.0000995

AC:

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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

AF:

0.000925

AC:

141

AN:

152354

Hom.:

Cov.:

AF XY:

0.000966

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00329

AC:

137

AN:

41590

American (AMR)

AF:

0.000131

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00121

Hom.:

Bravo

AF:

0.00103

ESP6500AA

AF:

0.00251

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000297

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Maturity-onset diabetes of the young (2)

not provided (2)

HNF1A-related disorder (1)

Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.27

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.39

PhyloP100

1.4

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.38

Sift

Benign

0.048

Sift4G

Benign

0.46

Polyphen

0.018

Vest4

0.25

MutPred

0.44

Loss of glycosylation at S581 (P = 0.0238)

MVP

0.84

MPC

0.14

ClinPred

0.056

GERP RS

2.4

gMVP

0.43

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over