12-120996568-C-T

Position:

• chr12-120996568-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3 BA1 BP2

This summary comes from the ClinGen Evidence Repository: The c.1135C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to serine at codon 379 (p.(Pro379Ser)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0001567, which is greater than the MDEP threshold for BA1 (0.0001)(BA1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has been observed in unknown phase with the variant c.872dup, p.Gly292Argfs*25 (internal lab contributors), which is classified as pathogenic by the ClinGen MDEP (BP2). This variant was identified in at least 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because the variant does not meet the PM2_Supporting cutoff (PMID 18003757, internal lab contributors). In summary, c.1135C>T meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BA1, BP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831956/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:1 B:1
• Conservation: PhyloP100: 7.89

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.1135C>T	p.Pro379Ser	missense_variant	6/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.1135C>T	p.Pro379Ser	missense_variant	6/10		NP_001293108.2
HNF1A	NM_001406915.1	c.1135C>T	p.Pro379Ser	missense_variant	6/9		NP_001393844.1
HNF1A	XM_024449168.2	c.1135C>T	p.Pro379Ser	missense_variant	6/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1135C>T	p.Pro379Ser	missense_variant	6/10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000360 AC: 9 AN: 250080 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135380

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461638 Hom.: 0 Cov.: 36 AF XY: 0.0000248 AC XY: 18 AN XY: 727136

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 20, 2022	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro379 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15883474, 21683639, 30293189). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HNF1A protein function. This missense change has been observed in individual(s) with maturity onset diabetes of the young (PMID: 18003757). This variant is present in population databases (rs754729248, gnomAD 0.02%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 379 of the HNF1A protein (p.Pro379Ser). -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 13, 2023	- -

Monogenic diabetes Benign:1

Benign, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Aug 01, 2024

The c.1135C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to serine at codon 379 (p.(Pro379Ser)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0001567, which is greater than the MDEP threshold for BA1 (0.0001)(BA1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has been observed in unknown phase with the variant c.872dup, p.Gly292Argfs*25 (internal lab contributors), which is classified as pathogenic by the ClinGen MDEP (BP2). This variant was identified in at least 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because the variant does not meet the PM2_Supporting cutoff (PMID 18003757, internal lab contributors). In summary, c.1135C>T meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BA1, BP2, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;D;D;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.1	D;.;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Benign	0.094	T;T;T;T
Polyphen		1.0	.;.;.;D
Vest4		0.92
MutPred		0.93		Loss of catalytic residue at P378 (P = 0.0193);Loss of catalytic residue at P378 (P = 0.0193);Loss of catalytic residue at P378 (P = 0.0193);Loss of catalytic residue at P378 (P = 0.0193);
MVP		0.98
MPC		0.57
ClinPred		0.88	D
GERP RS		4.6
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs754729248; hg19: chr12-121434371;