chr12-120999464-G-A

Variant names:

• chr12-120999464-G-A
• rs193922586
• ENST00000544413.2:c.1626G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001306179.2(HNF1A):​c.1626G>A​(p.Glu542Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,613,888 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00088 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (35 hom.)
• Consequence: HNF1A NM_001306179.2 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.20

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-120999464-G-A is Benign according to our data. Variant chr12-120999464-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-120999464-G-A is described in Lovd as [Likely_benign]. Variant chr12-120999464-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00088 (134/152328) while in subpopulation SAS AF= 0.024 (116/4828). AF 95% confidence interval is 0.0205. There are 3 homozygotes in gnomad4. There are 91 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 134 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.1624-19G>A		intron_variant	Intron 8 of 9	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.1626G>A	p.Glu542Glu	splice_region_variant, synonymous_variant	Exon 9 of 10		NP_001293108.2
HNF1A	XM_024449168.2	c.1698G>A	p.Glu566Glu	synonymous_variant	Exon 8 of 9		XP_024304936.1
HNF1A	NM_001406915.1	c.1432-19G>A		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.1624-19G>A		intron_variant	Intron 8 of 9	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes AF: 0.000880 AC: 134 AN: 152210 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0240

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00248 AC: 621 AN: 250716 Hom.: 12 AF XY: 0.00348 AC XY: 472 AN XY: 135696

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.000490

Gnomad SAS exome AF: 0.0192

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00130 AC: 1907 AN: 1461560 Hom.: 35 Cov.: 70 AF XY: 0.00187 AC XY: 1357 AN XY: 727094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.00195

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152328 Hom.: 3 Cov.: 33 AF XY: 0.00122 AC XY: 91 AN XY: 74480

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0240

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000317 Hom.: 0

Bravo AF: 0.000208

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Dec 03, 2015

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HNF1A c.1624-19G>A alters a nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0025 in 250746 control chromosomes in the gnomAD database, including 12 homozygotes. The observed variant frequency is approximately 99 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 36807). Based on the evidence outlined above, the variant was classified as benign. -

Mar 24, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity onset diabetes mellitus in young Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

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 rs193922586 with MODY3. -

not provided Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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	-0.83
CADD	Benign	0.97
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193922586; hg19: chr12-121437267;