rs55834942

Variant names:

• chr12-120999311-G-A
• rs55834942
• NM_000545.8:c.1545G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-120999311-G-A
• chr12-120999311-G-T
• chr12-120999311-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_000545.8(HNF1A):​c.1545G>A​(p.Thr515Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,613,798 control chromosomes in the GnomAD database, including 26,177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T515T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.13 (1790 hom., cov: 32)
  • Exomes 𝑓: 0.17 (24387 hom.)
• Consequence: HNF1A NM_000545.8 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -1.47
• Publications: 26 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015262663).
• BP6: Variant 12-120999311-G-A is Benign according to our data. Variant chr12-120999311-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129232.
• BP7: Synonymous conserved (PhyloP=-1.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

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.1545G>A	p.Thr515Thr	synonymous	Exon 8 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.1545G>A	p.Thr515Thr	synonymous	Exon 8 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.1353G>A	p.Thr451Thr	synonymous	Exon 7 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.1545G>A	p.Thr515Thr	synonymous	Exon 8 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.1545G>A	p.Thr515Thr	synonymous	Exon 8 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000540108.1	TSL:1	n.*985G>A		non_coding_transcript_exon	Exon 7 of 9	ENSP00000445445.1	P20823-8

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20000 AN: 151990 Hom.: 1789 Cov.: 32

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0378

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.152

GnomAD2 exomes AF: 0.140 AC: 35137 AN: 251142 AF XY: 0.141

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.0887

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.223

Gnomad NFE exome AF: 0.196

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.174 AC: 253901 AN: 1461690 Hom.: 24387 Cov.: 49 AF XY: 0.171 AC XY: 124242 AN XY: 727154

African (AFR) AF: 0.0288 AC: 964 AN: 33480

American (AMR) AF: 0.0922 AC: 4124 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 5692 AN: 26136

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.0430 AC: 3705 AN: 86258

European-Finnish (FIN) AF: 0.227 AC: 12084 AN: 53258

Middle Eastern (MID) AF: 0.166 AC: 960 AN: 5768

European-Non Finnish (NFE) AF: 0.194 AC: 216264 AN: 1111974

Other (OTH) AF: 0.167 AC: 10099 AN: 60394

GnomAD4 genome AF: 0.131 AC: 19992 AN: 152108 Hom.: 1790 Cov.: 32 AF XY: 0.128 AC XY: 9510 AN XY: 74360

African (AFR) AF: 0.0320 AC: 1329 AN: 41530

American (AMR) AF: 0.116 AC: 1768 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 748 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5178

South Asian (SAS) AF: 0.0380 AC: 183 AN: 4816

European-Finnish (FIN) AF: 0.222 AC: 2345 AN: 10578

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13137 AN: 67954

Other (OTH) AF: 0.150 AC: 317 AN: 2108

Alfa AF: 0.168 Hom.: 6054

Bravo AF: 0.122

TwinsUK AF: 0.191 AC: 707

ALSPAC AF: 0.200 AC: 772

ESP6500AA AF: 0.0397 AC: 175

ESP6500EA AF: 0.192 AC: 1654

ExAC AF: 0.140 AC: 16968

Asia WGS AF: 0.0270 AC: 97 AN: 3478

EpiCase AF: 0.203

EpiControl AF: 0.203

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Maturity-onset diabetes of the young type 3 (2)
-	1	-	Insulin-resistant diabetes mellitus (1)
-	-	1	Maturity-onset diabetes of the young (1)
-	-	1	Nonpapillary renal cell carcinoma (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.5
DANN	Benign	0.88
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0015	T
PhyloP100		-1.5
Sift4G	Benign	0.33	T
Vest4		0.26
GERP RS		-7.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55834942; hg19: chr12-121437114; COSMIC: COSV56566403; COSMIC: COSV56566403;