12-120997547-C-G

Variant names:

• chr12-120997547-C-G
• rs772756175
• NM_000545.8:c.1383C>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP7 BS2

The NM_000545.8(HNF1A):​c.1383C>G​(p.Pro461Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P461P) has been classified as Likely benign. The gene HNF1A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HNF1A NM_000545.8 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -7.30
• Publications: 0 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

Specifications for HNF1A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP7: Synonymous conserved (PhyloP=-7.3 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 5 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.1383C>G	p.Pro461Pro	synonymous	Exon 7 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.1383C>G	p.Pro461Pro	synonymous	Exon 7 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.1309+805C>G		intron	N/A	NP_001393844.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.1383C>G	p.Pro461Pro	synonymous	Exon 7 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.1383C>G	p.Pro461Pro	synonymous	Exon 7 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000535955.5	TSL:1	n.99C>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461268 Hom.: 0 Cov.: 38 AF XY: 0.00000275 AC XY: 2 AN XY: 727000

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52976

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.27
DANN	Benign	0.81
PhyloP100		-7.3

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: rs772756175; hg19: chr12-121435350;