12-120993601-G-T

Position:

• chr12-120993601-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000545.8(HNF1A):​c.608G>T​(p.Arg203Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R203C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.42

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a region_of_interest Interaction with DNA (size 3) in uniprot entity HNF1A_HUMAN there are 9 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, 0.969
• PP5: Variant 12-120993601-G-T is Pathogenic according to our data. Variant chr12-120993601-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1256577.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.608G>T	p.Arg203Leu	missense_variant	3/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.608G>T	p.Arg203Leu	missense_variant	3/10		NP_001293108.2
HNF1A	NM_001406915.1	c.608G>T	p.Arg203Leu	missense_variant	3/9		NP_001393844.1
HNF1A	XM_024449168.2	c.608G>T	p.Arg203Leu	missense_variant	3/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.608G>T	p.Arg203Leu	missense_variant	3/10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 02, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg203 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been observed in individuals with HNF1A-related conditions (PMID: 21168233, 30293189, 31363388), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HNF1A protein function. ClinVar contains an entry for this variant (Variation ID: 1256577). This missense change has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 203 of the HNF1A protein (p.Arg203Leu). -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 23, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;D;T;D;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.9	D;.;.;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;.;.;D;D
Sift4G	Uncertain	0.039	D;D;D;D;D
Polyphen		0.014	.;.;.;.;B
Vest4		0.94
MutPred		0.82		Loss of disorder (P = 0.0432);Loss of disorder (P = 0.0432);Loss of disorder (P = 0.0432);Loss of disorder (P = 0.0432);Loss of disorder (P = 0.0432);
MVP		1.0
MPC		1.2
ClinPred		0.99	D
GERP RS		4.5
gMVP		0.99

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-121431404; COSMIC: COSV57460658; COSMIC: COSV57460658;