rs377129682

chr12-120978953-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1 BP6_Very_Strong BS2

The NM_000545.8(HNF1A):c.185A>G(p.Asn62Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000193 in 1,609,220 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:1
• Conservation: PhyloP100: 4.16

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

Verdict is Benign. Variant got -10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000545.8
• BP6: Variant 12-120978953-A-G is Benign according to our data. Variant chr12-120978953-A-G is described in ClinVar as [Benign]. Clinvar id is 447485.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-120978953-A-G is described in Lovd as [Likely_pathogenic].
• BS2: High AC in GnomAd at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.185A>G	p.Asn62Ser	missense_variant	1/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.185A>G	p.Asn62Ser	missense_variant	1/10
HNF1A	NM_001406915.1	c.185A>G	p.Asn62Ser	missense_variant	1/9
HNF1A	XM_024449168.2	c.185A>G	p.Asn62Ser	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.185A>G	p.Asn62Ser	missense_variant	1/10	1	NM_000545.8	P4
HNF1A-AS1	ENST00000619441.1	n.128+1691T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000128 AC: 30 AN: 234674 Hom.: 0 AF XY: 0.000117 AC XY: 15 AN XY: 127964

Gnomad AFR exome AF: 0.000133

Gnomad AMR exome AF: 0.0000912

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000570

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.000196 AC: 285 AN: 1457208 Hom.: 0 Cov.: 35 AF XY: 0.000179 AC XY: 130 AN XY: 724590

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000688

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0000584

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000214

Gnomad4 OTH exome AF: 0.000548

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152012 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74264

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000220 Hom.: 0

Bravo AF: 0.000181

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000907 AC: 11

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 02, 2017

- -

Maturity onset diabetes mellitus in young Uncertain:1

Uncertain significance, 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. Sufficient evidence is found to confer the association of this particular variant rs377129682 with MODY3. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2022

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 62 of the HNF1A protein (p.Asn62Ser). This variant is present in population databases (rs377129682, gnomAD 0.02%). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 32910913). ClinVar contains an entry for this variant (Variation ID: 447485). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HNF1A function (PMID: 27899486, 32910913). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Monogenic diabetes Benign:1

Benign, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Jun 03, 2022

The c.185A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to serine at codon 62 (p.(Asn62Ser)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00019, which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). Furthermore, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.185A>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): BA1, BP5. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T
MetaSVM	Pathogenic	0.90	D
MutationTaster	Benign	0.93	D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N;.;.;.;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.043	D;.;.;.;D;D
Sift4G	Benign	0.11	T;T;T;T;T;T
Polyphen		0.37	.;.;.;.;.;B
Vest4		0.48
MVP		0.87
MPC		0.23
ClinPred		0.11	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.80

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: rs377129682; hg19: chr12-121416756;