12-120979044-C-T

Variant names:

• chr12-120979044-C-T
• rs34056805
• NM_000545.8:c.276C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000545.8(HNF1A):​c.276C>T​(p.Leu92Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000489 in 1,612,340 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: HNF1A NM_000545.8 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0540
• 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-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 12-120979044-C-T is Benign according to our data. Variant chr12-120979044-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.054 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00251 (383/152338) while in subpopulation AFR AF = 0.00856 (356/41570). AF 95% confidence interval is 0.00783. There are 2 homozygotes in GnomAd4. There are 175 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 383 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	NM_000545.8	MANE Select	c.276C>T	p.Leu92Leu	synonymous	Exon 1 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.276C>T	p.Leu92Leu	synonymous	Exon 1 of 10	NP_001293108.2
	HNF1A	NM_001406915.1		c.276C>T	p.Leu92Leu	synonymous	Exon 1 of 9	NP_001393844.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.276C>T	p.Leu92Leu	synonymous	Exon 1 of 10	ENSP00000257555.5
	HNF1A	ENST00000544413.2	TSL:1	c.276C>T	p.Leu92Leu	synonymous	Exon 1 of 10	ENSP00000438804.1
	HNF1A	ENST00000538646.5	TSL:1	n.276C>T		non_coding_transcript_exon	Exon 1 of 6	ENSP00000443964.1

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 382 AN: 152220 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00856

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000696 AC: 169 AN: 242784 AF XY: 0.000492

Gnomad AFR exome AF: 0.00852

Gnomad AMR exome AF: 0.000820

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000277

Gnomad OTH exome AF: 0.000504

GnomAD4 exome AF: 0.000277 AC: 405 AN: 1460002 Hom.: 1 Cov.: 35 AF XY: 0.000231 AC XY: 168 AN XY: 726158

African (AFR) AF: 0.00721 AC: 241 AN: 33446

American (AMR) AF: 0.000877 AC: 39 AN: 44446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 85862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53118

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.0000720 AC: 80 AN: 1111328

Other (OTH) AF: 0.000630 AC: 38 AN: 60306

GnomAD4 genome AF: 0.00251 AC: 383 AN: 152338 Hom.: 2 Cov.: 32 AF XY: 0.00235 AC XY: 175 AN XY: 74498

African (AFR) AF: 0.00856 AC: 356 AN: 41570

American (AMR) AF: 0.00137 AC: 21 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00111 Hom.: 1

Bravo AF: 0.00262

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Maturity onset diabetes mellitus in young (2)
-	-	2	Maturity-onset diabetes of the young type 3 (2)
-	-	1	Nonpapillary renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.9
DANN	Benign	0.90
PhyloP100		-0.054
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs34056805; hg19: chr12-121416847;