12-120988940-C-T

Position:

• chr12-120988940-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS4_Moderate PP1_Strong PM1 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.434C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to phenylalanine at codon 145 (p.(Ser145Phe)) of NM_000545.8. This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID:28701371, internal lab contributors). This variant segregated with diabetes, with 4 informative meioses in 2 families with MODY (PP1_Strong; PMID:28701371, internal lab contributors). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.989, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.433T>C (p.(Ser145Pro)), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. This variant was identified in at least six individuals with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information, and PP4 cannot be applied (PMID:28701371, internal lab contributors). In summary, c.434C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved September 30, 2021): PP3, PM1, PM2_Supporting, PS4_Moderate, PP1_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386959990/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HNF1A ENST00000257555.11 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.50

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 Pathogenic. Variant got 10 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.434C>T	p.Ser145Phe	missense_variant	2/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.434C>T	p.Ser145Phe	missense_variant	2/10		NP_001293108.2
HNF1A	NM_001406915.1	c.434C>T	p.Ser145Phe	missense_variant	2/9		NP_001393844.1
HNF1A	XM_024449168.2	c.434C>T	p.Ser145Phe	missense_variant	2/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.434C>T	p.Ser145Phe	missense_variant	2/10	1	NM_000545.8	ENSP00000257555	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 08, 2022

The c.434C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to phenylalanine at codon 145 (p.(Ser145Phe)) of NM_000545.8. This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 28701371, internal lab contributors). This variant segregated with diabetes, with 4 informative meioses in 2 families with MODY (PP1_Strong; PMID: 28701371, internal lab contributors). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.989, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.433T>C (p.(Ser145Pro)), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. This variant was identified in at least six individuals with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information, and PP4 cannot be applied (PMID:28701371, internal lab contributors). In summary, c.434C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved September 30, 2021): PP3, PM1, PM2_Supporting, PS4_Moderate, PP1_Strong. -

Maturity onset diabetes mellitus in young Pathogenic:1

Likely risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

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 rs1555211426 with MODY3. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 30, 2022

This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and appears to segregate with disease in at least one family (personal communication related to ClinVar ID 447489, lab code: 508240). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). The variant is located in a region that is considered important for protein function and/or structure. Computational tools predict that this variant is damaging. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;D;D;D;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.7	D;.;.;.;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D
Vest4		0.99
MutPred		0.88		Loss of disorder (P = 0.0045);Loss of disorder (P = 0.0045);Loss of disorder (P = 0.0045);Loss of disorder (P = 0.0045);Loss of disorder (P = 0.0045);Loss of disorder (P = 0.0045);
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		5.1
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555211426; hg19: chr12-121426743; COSMIC: COSV57462866;