rs193922587

Variant names:

• chr12-120999522-C-T
• rs193922587
• NM_000545.8:c.1663C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. BP5 PM2_Supporting BS2

This summary comes from the ClinGen Evidence Repository: The c.1663C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to phenylalanine at codon 555(p.(Leu555Phe)) of NM_000545.8. This variant has an allele frequency of 0.00001797 in Non-Finnish Europeans, below the MDEP threshold of 0.00002, and no copies in other subpopulations, in gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in the homozygous state in a 56 year old normoglycemic individual (BS2; PMID:22341299). Lastly, this variant was identified in a patient with an alternate molecular basis for disease (BP5; PMID:22341299). This variant was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant has a REVEL score of 0.5809, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.1663C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PM2_Supporting, BS2, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA214281/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:2 B:2 O:1
• Conservation: PhyloP100: 0.975
• 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]

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: Likely_benign. The variant received -4 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

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.1663C>T	p.Leu555Phe	missense	Exon 9 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.1684C>T	p.Leu562Phe	missense	Exon 9 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.1471C>T	p.Leu491Phe	missense	Exon 8 of 9	NP_001393844.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.1663C>T	p.Leu555Phe	missense	Exon 9 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.1684C>T	p.Leu562Phe	missense	Exon 9 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000540108.1	TSL:1	n.*1103C>T		non_coding_transcript_exon	Exon 8 of 9	ENSP00000445445.1	P20823-8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000806 AC: 2 AN: 248172 AF XY: 0.00000743

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461242 Hom.: 0 Cov.: 69 AF XY: 0.0000179 AC XY: 13 AN XY: 726932

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

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111906

Other (OTH) AF: 0.0000166 AC: 1 AN: 60364

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000235 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	Maturity-onset diabetes of the young type 3 (2)
-	-	1	HNF1A-related disorder (1)
-	1	-	Maturity-onset diabetes of the young (1)
-	-	1	Monogenic diabetes (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	-0.048	T
PhyloP100		0.97
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.93	N
REVEL	Uncertain	0.58
Sift	Uncertain	0.022	D
Sift4G	Benign	0.098	T
Polyphen		0.90	P
Vest4		0.37
MutPred		0.60		Loss of glycosylation at T564 (P = 0.1007)
MVP		0.99
MPC		0.39
ClinPred		0.77	D
GERP RS		3.6
gMVP		0.61
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs193922587; hg19: chr12-121437325;