12-120978797-C-G

Variant names:

• chr12-120978797-C-G
• rs774637975
• NM_000545.8:c.29C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_000545.8(HNF1A):​c.29C>G​(p.Thr10Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T10P) has been classified as Likely pathogenic. The gene HNF1A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.46
• Publications: 13 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

Specifications for HNF1A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000545.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-120978796-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1675061.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20703882).

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.29C>G	p.Thr10Arg	missense	Exon 1 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.29C>G	p.Thr10Arg	missense	Exon 1 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.29C>G	p.Thr10Arg	missense	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.29C>G	p.Thr10Arg	missense	Exon 1 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.29C>G	p.Thr10Arg	missense	Exon 1 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000538626.2	TSL:1	n.147C>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460820 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726738

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111884

Other (OTH) AF: 0.00 AC: 0 AN: 60366

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	0.0025	D
PhyloP100		2.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.22	N
REVEL	Uncertain	0.47
Sift	Benign	0.56	T
Sift4G	Benign	0.83	T
Polyphen		0.0040	B
Vest4		0.16
MutPred		0.51		Gain of MoRF binding (P = 0.0173)
MVP		0.83
MPC		0.19
ClinPred		0.39	T
GERP RS		3.4
PromoterAI		0.018	Neutral
gMVP		0.71
Mutation Taster		=11/89	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: rs774637975; hg19: chr12-121416600;