NM_000545.8:c.293C>G

Variant names:

• chr12-120979061-C-G
• rs1800574
• NM_000545.8:c.293C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000545.8(HNF1A):​c.293C>G​(p.Ala98Gly) variant causes a missense change involving the alteration of a 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A98V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.35
• 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]

HNF1A-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.293C>G	p.Ala98Gly	missense	Exon 1 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.293C>G	p.Ala98Gly	missense	Exon 1 of 10	NP_001293108.2
	HNF1A	NM_001406915.1		c.293C>G	p.Ala98Gly	missense	Exon 1 of 9	NP_001393844.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.293C>G	p.Ala98Gly	missense	Exon 1 of 10	ENSP00000257555.5
	HNF1A	ENST00000544413.2	TSL:1	c.293C>G	p.Ala98Gly	missense	Exon 1 of 10	ENSP00000438804.1
	HNF1A	ENST00000538646.5	TSL:1	n.293C>G		non_coding_transcript_exon	Exon 1 of 6	ENSP00000443964.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.11	T
Polyphen		0.093	B
Vest4		0.47
MutPred		0.69		Loss of stability (P = 0.0277)
MVP		0.85
MPC		0.19
ClinPred		0.98	D
GERP RS		4.5
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
gMVP		0.87
Mutation Taster		=55/45	polymorphism

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: rs1800574; hg19: chr12-121416864; COSMIC: COSV57464195;