chr12-120999392-A-G

Variant names:

• chr12-120999392-A-G
• rs886038347
• NM_000545.8:c.1623+3A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. BP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1623+3A>G variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 8 of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.0 for donor loss, suggesting that the variant has no impact on splicing (BP4). In summary, c.1623+3A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM2_Supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10587145/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNF1A NM_000545.8 splice_region, intron
• Scores: Splicing: ADA: 0.8319
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1
• Conservation: PhyloP100: 4.35
• 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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.1623+3A>G		splice_region_variant, intron_variant	Intron 8 of 9	ENST00000257555.11	NP_000536.6
HNF1A	XM_024449168.2	c.1626A>G	p.Val542Val	synonymous_variant	Exon 8 of 9		XP_024304936.1
HNF1A	NM_001306179.2	c.1623+3A>G		splice_region_variant, intron_variant	Intron 8 of 9		NP_001293108.2
HNF1A	NM_001406915.1	c.1431+3A>G		splice_region_variant, intron_variant	Intron 7 of 8		NP_001393844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1623+3A>G		splice_region_variant, intron_variant	Intron 8 of 9	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 56

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Maturity onset diabetes mellitus in young Uncertain:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs886038347 with MODY3. -

Monogenic diabetes Uncertain:1

May 03, 2022

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.1623+3A>G variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 8 of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.0 for donor loss, suggesting that the variant has no impact on splicing (BP4). In summary, c.1623+3A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM2_Supporting, BP4. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Benign	0.92
PhyloP100		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.83
dbscSNV1_RF	Benign	0.41
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: rs886038347; hg19: chr12-121437195;