chr12-120999579-A-C

Variant names:

• chr12-120999579-A-C
• rs1169305
• NM_000545.8:c.1720A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000545.8(HNF1A):​c.1720A>C​(p.Ser574Arg) 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 benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S574D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.738
• Publications: 65 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18867612).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	NM_000545.8	MANE Select	c.1720A>C	p.Ser574Arg	missense	Exon 9 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.1741A>C	p.Ser581Arg	missense	Exon 9 of 10	NP_001293108.2
	HNF1A	NM_001406915.1		c.1528A>C	p.Ser510Arg	missense	Exon 8 of 9	NP_001393844.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.1720A>C	p.Ser574Arg	missense	Exon 9 of 10	ENSP00000257555.5
	HNF1A	ENST00000544413.2	TSL:1	c.1741A>C	p.Ser581Arg	missense	Exon 9 of 10	ENSP00000438804.1
	HNF1A	ENST00000540108.1	TSL:1	n.*1160A>C		non_coding_transcript_exon	Exon 8 of 9	ENSP00000445445.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 56

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.27	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.52	T
PhyloP100		0.74
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.36
Sift	Benign	0.048	D
Sift4G	Benign	0.46	T
Polyphen		0.018	B
Vest4		0.25
MutPred		0.44		Loss of glycosylation at S581 (P = 0.0238)
MVP		0.79
MPC		0.14
ClinPred		0.28	T
GERP RS		2.6
gMVP		0.43
Mutation Taster		=100/0	polymorphism

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: rs1169305; hg19: chr12-121437382;