NM_000545.8:c.1780A>G

Variant names:

• chr12-121001076-A-G
• rs751112023
• NM_000545.8:c.1780A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 2P and 14B. PM5 BP4_Moderate BP6_Very_Strong BS2

The NM_000545.8(HNF1A):​c.1780A>G​(p.Ser594Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S594R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: 5.82
• Publications: 4 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]

C12orf43 (HGNC:25719): (chromosome 12 open reading frame 43) Predicted to be involved in Spemann organizer formation and negative regulation of Wnt signaling pathway. Predicted to be located in nuclear envelope. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-121001077-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1315998.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22481379).
• BP6: Variant 12-121001076-A-G is Benign according to our data. Variant chr12-121001076-A-G is described in ClinVar as Benign. ClinVar VariationId is 1700002.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High AC in GnomAdExome4 at 17 AD,Unknown gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	NM_000545.8	MANE Select	c.1780A>G	p.Ser594Gly	missense	Exon 10 of 10	NP_000536.6
	C12orf43	NM_022895.3	MANE Select	c.*3077T>C		3_prime_UTR	Exon 6 of 6	NP_075046.1
	HNF1A	NM_001306179.2		c.1801A>G	p.Ser601Gly	missense	Exon 10 of 10	NP_001293108.2	F5H0K0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.1780A>G	p.Ser594Gly	missense	Exon 10 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.1801A>G	p.Ser601Gly	missense	Exon 10 of 10	ENSP00000438804.1	F5H0K0
	C12orf43	ENST00000288757.7	TSL:1 MANE Select	c.*3077T>C		3_prime_UTR	Exon 6 of 6	ENSP00000288757.5	Q96C57

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000560 AC: 14 AN: 250012 AF XY: 0.0000518

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

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: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461280 Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9 AN XY: 726936

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000380 AC: 17 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53006

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111858

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.0041	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.76	D
PhyloP100		5.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.58
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.42
MutPred		0.46		Loss of phosphorylation at S601 (P = 0.017)
MVP		0.89
MPC		0.19
ClinPred		0.37	T
GERP RS		6.1
gMVP		0.75
Mutation Taster		=37/63	disease causing

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: rs751112023; hg19: chr12-121438879;