rs377129682

Variant names:

• chr12-120978953-A-G
• rs377129682
• NM_000545.8:c.185A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP5

This summary comes from the ClinGen Evidence Repository: 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). Functional studies demonstrated the p.Asn62Ser protein has 65% transcriptional activity and 70% nuclear localization of wildtype; however, this is between the ClinGen MDEP cutoffs for PS3 and BS3 (PMID:27899486). This variant has a REVEL score of 0.555, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (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 2.1.0, approved 8/11/2023): BA1, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831682/MONDO:0015967/017

• 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:2 B:2
• Conservation: PhyloP100: 4.16
• Publications: 7 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

Our verdict: Benign. The variant received -9 ACMG points.

• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.185A>G	p.Asn62Ser	missense	Exon 1 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.185A>G	p.Asn62Ser	missense	Exon 1 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.185A>G	p.Asn62Ser	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.185A>G	p.Asn62Ser	missense	Exon 1 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.185A>G	p.Asn62Ser	missense	Exon 1 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000538646.5	TSL:1	n.185A>G		non_coding_transcript_exon	Exon 1 of 6	ENSP00000443964.1	P20823-4

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

GnomAD2 exomes AF: 0.000128 AC: 30 AN: 234674 AF XY: 0.000117

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 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

African (AFR) AF: 0.0000897 AC: 3 AN: 33452

American (AMR) AF: 0.0000688 AC: 3 AN: 43606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25968

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39614

South Asian (SAS) AF: 0.0000584 AC: 5 AN: 85688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52878

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.000214 AC: 238 AN: 1110050

Other (OTH) AF: 0.000548 AC: 33 AN: 60192

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

African (AFR) AF: 0.0000483 AC: 2 AN: 41410

American (AMR) AF: 0.000131 AC: 2 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000242 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

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Maturity-onset diabetes of the young (1)
-	-	1	Monogenic diabetes (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Pathogenic	0.90	D
PhyloP100		4.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.56
Sift	Benign	0.043	D
Sift4G	Benign	0.11	T
Polyphen		0.37	B
Vest4		0.48
MVP		0.87
MPC		0.23
ClinPred		0.11	T
GERP RS		4.3
PromoterAI		-0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.80
Mutation Taster		=0/100	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: rs377129682; hg19: chr12-121416756;