rs3999413

Variant names:

• chr12-121000135-G-A
• rs3999413
• NM_000545.8:c.1768+508G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000545.8(HNF1A):​c.1768+508G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 152,176 control chromosomes in the GnomAD database, including 1,761 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1761 hom., cov: 32)
• Consequence: HNF1A NM_000545.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.838
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.1768+508G>A		intron_variant	Intron 9 of 9	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.1789+508G>A		intron_variant	Intron 9 of 9		NP_001293108.2
HNF1A	NM_001406915.1	c.1576+508G>A		intron_variant	Intron 8 of 8		NP_001393844.1
HNF1A	XM_024449168.2	c.1861+508G>A		intron_variant	Intron 8 of 8		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1768+508G>A		intron_variant	Intron 9 of 9	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19952 AN: 152058 Hom.: 1760 Cov.: 32

Gnomad AFR AF: 0.0335

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.0813

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.115

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.131 AC: 19957 AN: 152176 Hom.: 1761 Cov.: 32 AF XY: 0.132 AC XY: 9827 AN XY: 74390

African (AFR) AF: 0.0334 AC: 1387 AN: 41542

American (AMR) AF: 0.0811 AC: 1241 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 425 AN: 3468

East Asian (EAS) AF: 0.130 AC: 673 AN: 5174

South Asian (SAS) AF: 0.158 AC: 761 AN: 4816

European-Finnish (FIN) AF: 0.190 AC: 2012 AN: 10580

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 12989 AN: 67984

Other (OTH) AF: 0.114 AC: 240 AN: 2108

Alfa AF: 0.154 Hom.: 393

Bravo AF: 0.115

Asia WGS AF: 0.104 AC: 360 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.44
DANN	Benign	0.66
PhyloP100		-0.84
Mutation Taster		=100/0	polymorphism (auto)

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: rs3999413; hg19: chr12-121437938;