rs587778395

Variant names:

• chr12-121001192-A-G
• rs587778395
• NM_000545.8:c.1896A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-121001192-A-G
• chr12-121001192-A-C
• chr12-121001192-A-T

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP7

This summary comes from the ClinGen Evidence Repository: The c.1896A>G variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 632 (p.Ter632=) of NM_000545.8. This synonymous variant is not predicted by SpliceAI to impact splicing (BP7). The frequency of the c.1896A>G variant in gnomAD v2.1.1 is 0.0000265 in Non-Finnish Europeans, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. In summary, c.1896A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA160007/MONDO:0015967/017

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: HNF1A NM_000545.8 stop_retained
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 B:1 O:1
• Conservation: PhyloP100: 2.80
• Publications: 2 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]

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received -1 ACMG points.

• BP7: For more information check the summary or visit ClinGen Evidence Repository.

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.1896A>G	p.Ter632Ter	stop_retained	Exon 10 of 10	NP_000536.6
	C12orf43	NM_022895.3	MANE Select	c.*2961T>C		3_prime_UTR	Exon 6 of 6	NP_075046.1
	HNF1A	NM_001306179.2		c.1917A>G	p.Ter639Ter	stop_retained	Exon 10 of 10	NP_001293108.2	F5H0K0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.1896A>G	p.Ter632Ter	stop_retained	Exon 10 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.1917A>G	p.Ter639Ter	stop_retained	Exon 10 of 10	ENSP00000438804.1	F5H0K0
	C12orf43	ENST00000288757.7	TSL:1 MANE Select	c.*2961T>C		3_prime_UTR	Exon 6 of 6	ENSP00000288757.5	Q96C57

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152056 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250476 AF XY: 0.00000738

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: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461638 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727120

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111936

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152056 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74262

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000288 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Maturity-onset diabetes of the young (1)
-	1	-	Monogenic diabetes (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	10
DANN	Benign	0.76
PhyloP100		2.8

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: rs587778395; hg19: chr12-121438995;