12-120994237-C-G

Variant names:

• chr12-120994237-C-G
• rs771108132
• NM_000545.8:c.787C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000545.8(HNF1A):​c.787C>G​(p.Arg263Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R263L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43
• Publications: 1 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_000545.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-120994238-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1676718.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.787C>G	p.Arg263Gly	missense_variant	Exon 4 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.787C>G	p.Arg263Gly	missense_variant	Exon 4 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.787C>G	p.Arg263Gly	missense_variant	Exon 4 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.787C>G	p.Arg263Gly	missense_variant	Exon 4 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.787C>G	p.Arg263Gly	missense_variant	Exon 4 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 04, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HNF1A c.787C>G (p.Arg263Gly) results in a non-conservative amino acid change located in the Homeobox domain (IPR001356) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249174 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.787C>G has been reported in the literature in an individual affected with hepatocellular carcinoma (Hechtman_2019). This report however, does not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes of the Young 3. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Other variants affecting the same codon have been reported in the ClinVar and HGMD databases (example: p.R263C, p.R263H, p.R263L) suggesting this residue may be clinically significant. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;D;D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.98	D
PhyloP100		2.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.5	D;.;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.96
MutPred		0.81		Loss of MoRF binding (P = 0.0069);Loss of MoRF binding (P = 0.0069);Loss of MoRF binding (P = 0.0069);Loss of MoRF binding (P = 0.0069);
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		4.8
gMVP		0.99
Mutation Taster		=5/95	disease causing

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: rs771108132; hg19: chr12-121432040; COSMIC: COSV57462916; COSMIC: COSV57462916;