rs137853242

Variant names:

• chr12-120999607-G-A
• rs137853242
• NM_000545.8:c.1748G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-120999607-G-A
• chr12-120999607-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000545.8(HNF1A):​c.1748G>A​(p.Arg583Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000856 in 1,611,350 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. R583G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (2 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5 B:5
• Conservation: PhyloP100: 2.07
• Publications: 21 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013279617).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000584 (89/152300) while in subpopulation AMR AF = 0.000915 (14/15298). AF 95% confidence interval is 0.000612. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 89 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	NM_000545.8	MANE Select	c.1748G>A	p.Arg583Gln	missense	Exon 9 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.1769G>A	p.Arg590Gln	missense	Exon 9 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.1556G>A	p.Arg519Gln	missense	Exon 8 of 9	NP_001393844.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.1748G>A	p.Arg583Gln	missense	Exon 9 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.1769G>A	p.Arg590Gln	missense	Exon 9 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000540108.1	TSL:1	n.*1188G>A		non_coding_transcript_exon	Exon 8 of 9	ENSP00000445445.1	P20823-8

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.000916

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: 0.000779

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000478 AC: 115 AN: 240352 AF XY: 0.000457

Gnomad AFR exome AF: 0.0000658

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000552

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000941

Gnomad OTH exome AF: 0.000338

GnomAD4 exome AF: 0.000885 AC: 1291 AN: 1459050 Hom.: 2 Cov.: 35 AF XY: 0.000851 AC XY: 618 AN XY: 725858

African (AFR) AF: 0.000120 AC: 4 AN: 33452

American (AMR) AF: 0.000336 AC: 15 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39686

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86152

European-Finnish (FIN) AF: 0.0000385 AC: 2 AN: 51886

Middle Eastern (MID) AF: 0.000188 AC: 1 AN: 5316

European-Non Finnish (NFE) AF: 0.00111 AC: 1233 AN: 1111522

Other (OTH) AF: 0.000531 AC: 32 AN: 60274

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000537 AC XY: 40 AN XY: 74464

African (AFR) AF: 0.000168 AC: 7 AN: 41562

American (AMR) AF: 0.000915 AC: 14 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68022

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000626 Hom.: 0

Bravo AF: 0.000669

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000699 AC: 6

ExAC AF: 0.000495 AC: 60

EpiCase AF: 0.000600

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	-	3	not specified (3)
2	-	-	Maturity-onset diabetes of the young type 3 (2)
-	1	-	Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C2675866:Type 1 diabetes mellitus 20 (1)
-	1	-	HNF1A-related disorder (1)
-	-	1	Maturity-onset diabetes of the young (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.13	D
PhyloP100		2.1
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.89	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.010	D
Sift4G	Benign	0.56	T
Polyphen		0.0050	B
Vest4		0.33
MVP		1.0
MPC		0.33
ClinPred		0.022	T
GERP RS		3.9
gMVP		0.74
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs137853242; hg19: chr12-121437410; COSMIC: COSV99983097; COSMIC: COSV99983097;