rs774637975

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-120978797-C-T
• chr12-120978797-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1_Supporting PM5_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The c.29C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to methionine at codon 10 (p.(Thr10Met)) of NM_000545.8. This variant is located within the dimerization domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).  Additionally, this variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). While the variant was identified in 5 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, PS4_Moderate could not be applied because c.29C>T does not meet the criteria to apply PM2_Supporting (≤0.00002 allele frequency in the European Non-Finnish population and ≤1 copy in any other subpopulation)(PMIDs 30155490, 18003757, internal lab contributors). Another missense variant, c.28A>C (p.Thr10Pro) has been interpreted as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM1_Supporting, PP4, PM5_Suppporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831654/MONDO:0015967/017

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:6
• 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 3 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

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>T	p.Thr10Met	missense	Exon 1 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.29C>T	p.Thr10Met	missense	Exon 1 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.29C>T	p.Thr10Met	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>T	p.Thr10Met	missense	Exon 1 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.29C>T	p.Thr10Met	missense	Exon 1 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000538626.2	TSL:1	n.147C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152158 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000202 AC: 5 AN: 247688 AF XY: 0.00000742

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1460818 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 726736

African (AFR) AF: 0.000119 AC: 4 AN: 33474

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

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

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

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: 0.0000117 AC: 13 AN: 1111884

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152158 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

African (AFR) AF: 0.0000483 AC: 2 AN: 41434

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000227 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	Maturity-onset diabetes of the young (2)
1	1	-	Maturity-onset diabetes of the young type 3 (2)
-	2	-	Monogenic diabetes (2)
-	1	-	Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.049
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	0.46	D
PhyloP100		2.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.047	D
Polyphen		0.96	D
Vest4		0.25
MVP		0.97
MPC		0.17
ClinPred		0.56	D
GERP RS		3.4
PromoterAI		-0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.58
Mutation Taster		=1/99	disease causing (ClinVar)

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; COSMIC: COSV99982822;