chr12-120999607-G-C

Position:

• chr12-120999607-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000545.8(HNF1A):​c.1748G>C​(p.Arg583Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,052 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R583G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.07

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 Uncertain_significance. Variant got 4 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.1748G>C	p.Arg583Pro	missense_variant	9/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.1769G>C	p.Arg590Pro	missense_variant	9/10		NP_001293108.2
HNF1A	NM_001406915.1	c.1556G>C	p.Arg519Pro	missense_variant	8/9		NP_001393844.1
HNF1A	XM_024449168.2	c.1841G>C	p.Arg614Pro	missense_variant	8/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1748G>C	p.Arg583Pro	missense_variant	9/10	1	NM_000545.8	ENSP00000257555	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459052 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 725858

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.56	.;D;.;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.84	T;T;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.73	D;D;D;D;D
MetaSVM	Uncertain	0.42	D
MutationTaster	Benign	0.85	N;N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.3	N;.;.;N;N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0040	D;.;.;D;D
Sift4G	Benign	0.35	T;T;T;T;T
Polyphen		0.47	.;.;.;.;P
Vest4		0.66
MutPred		0.64		.;.;.;.;Gain of relative solvent accessibility (P = 0.0166);
MVP		1.0
MPC		0.60
ClinPred		0.70	D
GERP RS		3.9
gMVP		0.78

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: chr12-121437410;