12-120978645-G-C

Variant names:

• chr12-120978645-G-C
• rs563304627
• NM_000545.8:c.-124G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000545.8(HNF1A):​c.-124G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 926,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: HNF1A NM_000545.8 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.36
• Publications: 3 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 12-120978645-G-C is Benign according to our data. Variant chr12-120978645-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1320426.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000263 (40/152242) while in subpopulation EAS AF = 0.00271 (14/5160). AF 95% confidence interval is 0.00164. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 40 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	NM_000545.8	MANE Select	c.-124G>C		5_prime_UTR	Exon 1 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.-124G>C		5_prime_UTR	Exon 1 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.-124G>C		5_prime_UTR	Exon 1 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.-124G>C		5_prime_UTR	Exon 1 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000560968.6	TSL:1	n.-124G>C		non_coding_transcript_exon	Exon 1 of 10	ENSP00000453965.2	E0YMI8
	HNF1A	ENST00000560968.6	TSL:1	n.-124G>C		5_prime_UTR	Exon 1 of 10	ENSP00000453965.2	E0YMI8

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00271

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000196 AC: 37 AN: 188332 AF XY: 0.000208

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00150

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000732

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000239 AC: 185 AN: 774312 Hom.: 0 Cov.: 11 AF XY: 0.000251 AC XY: 103 AN XY: 409910

African (AFR) AF: 0.0000483 AC: 1 AN: 20692

American (AMR) AF: 0.0000246 AC: 1 AN: 40650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21574

East Asian (EAS) AF: 0.00333 AC: 118 AN: 35412

South Asian (SAS) AF: 0.000515 AC: 36 AN: 69904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37614

Middle Eastern (MID) AF: 0.000262 AC: 1 AN: 3824

European-Non Finnish (NFE) AF: 0.0000474 AC: 24 AN: 506642

Other (OTH) AF: 0.000105 AC: 4 AN: 38000

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74444

African (AFR) AF: 0.0000241 AC: 1 AN: 41544

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

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

East Asian (EAS) AF: 0.00271 AC: 14 AN: 5160

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Benign	0.94
PhyloP100		1.4
PromoterAI		-0.0015	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.2
Mutation Taster		=59/241	disease causing

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: rs563304627; hg19: chr12-121416448;