12-120988897-C-G

Variant names:

• chr12-120988897-C-G
• NM_000545.8:c.391C>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000545.8(HNF1A):​c.391C>G​(p.Arg131Gly) 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. 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. R131Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0380

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a region_of_interest Interaction with DNA (size 2) in uniprot entity HNF1A_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.391C>G	p.Arg131Gly	missense_variant	Exon 2 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.391C>G	p.Arg131Gly	missense_variant	Exon 2 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.391C>G	p.Arg131Gly	missense_variant	Exon 2 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.391C>G	p.Arg131Gly	missense_variant	Exon 2 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.391C>G	p.Arg131Gly	missense_variant	Exon 2 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;D;T;D;T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.047
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.1	D;.;.;.;D;D
REVEL	Pathogenic	0.85
Sift	Benign	0.038	D;.;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D
Vest4		0.95
MutPred		0.90		Loss of catalytic residue at R131 (P = 0.0373);Loss of catalytic residue at R131 (P = 0.0373);Loss of catalytic residue at R131 (P = 0.0373);Loss of catalytic residue at R131 (P = 0.0373);Loss of catalytic residue at R131 (P = 0.0373);Loss of catalytic residue at R131 (P = 0.0373);
MVP		0.99
MPC		2.4
ClinPred		0.99	D
GERP RS		1.8
gMVP		0.95

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-121426700;