NM_000545.8:c.1896A>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_000545.8(HNF1A):​c.1896A>C​(p.Ter632Tyrext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNF1A NM_000545.8 stop_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.80
• Publications: 0 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_000545.8 Downstream stopcodon found after 706 codons.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	NM_000545.8	MANE Select	c.1896A>C	p.Ter632Tyrext*?	stop_lost	Exon 10 of 10	NP_000536.6
	C12orf43	NM_022895.3	MANE Select	c.*2961T>G		3_prime_UTR	Exon 6 of 6	NP_075046.1
	HNF1A	NM_001306179.2		c.1917A>C	p.Ter639Tyrext*?	stop_lost	Exon 10 of 10	NP_001293108.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.1896A>C	p.Ter632Tyrext*?	stop_lost	Exon 10 of 10	ENSP00000257555.5
	HNF1A	ENST00000544413.2	TSL:1	c.1917A>C	p.Ter639Tyrext*?	stop_lost	Exon 10 of 10	ENSP00000438804.1
	HNF1A	ENST00000540108.1	TSL:1	n.*1336A>C		non_coding_transcript_exon	Exon 9 of 9	ENSP00000445445.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	14
DANN	Benign	0.84
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		2.8
Vest4		0.45
GERP RS		4.9
Mutation Taster		=35/165	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: rs587778395; hg19: chr12-121438995;