12-120978860-G-C

Variant names:

• chr12-120978860-G-C
• rs137853247
• NM_000545.8:c.92G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000545.8(HNF1A):​c.92G>C​(p.Gly31Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. G31D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.06
• Publications: 34 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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000545.8
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24010026).

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.92G>C	p.Gly31Ala	missense	Exon 1 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.92G>C	p.Gly31Ala	missense	Exon 1 of 10	NP_001293108.2
	HNF1A	NM_001406915.1		c.92G>C	p.Gly31Ala	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.92G>C	p.Gly31Ala	missense	Exon 1 of 10	ENSP00000257555.5
	HNF1A	ENST00000544413.2	TSL:1	c.92G>C	p.Gly31Ala	missense	Exon 1 of 10	ENSP00000438804.1
	HNF1A	ENST00000538646.5	TSL:1	n.92G>C		non_coding_transcript_exon	Exon 1 of 6	ENSP00000443964.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248682 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461178 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726922

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

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52934

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111858

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000223 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	0.26	D
PhyloP100		3.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.71	N
REVEL	Uncertain	0.41
Sift	Benign	0.28	T
Sift4G	Benign	0.44	T
Polyphen		0.0070	B
Vest4		0.23
MutPred		0.56		Gain of sheet (P = 0.0221)
MVP		0.86
MPC		0.39
ClinPred		0.15	T
GERP RS		3.5
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
gMVP		0.79
Mutation Taster		=91/9	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: rs137853247; hg19: chr12-121416663;