NM_000545.8:c.871C>T

Variant names:

• chr12-120994321-C-T
• rs151256267
• NM_000545.8:c.871C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP2 BS3_Supporting BS1

This summary comes from the ClinGen Evidence Repository: The c.871C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to serine at codon 291 (p.(Pro291Ser)) of NM_000545.8. •This variant has been observed in unknown phase with the variant c.494G>A, p.Trp165Ter (internal lab contributors), which is classified as pathogenic by the ClinGen MDEP (BP2). Functional studies demonstrated the p.Pro291Ser protein has abnormal nuclear localization above 75% of wildtype, indicating that this variant does not impact protein function (PMID:32910913) (BS3_Supporting). Lastly, this variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00001163, which is greater than or equal to the MDEP threshold for BS1 (≥0.000033) (BS1). In summary, c.871C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/2021): BP2, BS3_Supporting, BS1 LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831856/MONDO:0007453/017

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Likely benign reviewed by expert panel B:8
• Conservation: PhyloP100: 0.661
• Publications: 15 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 Gene-Disease associations (from GenCC):

• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• type 1 diabetes mellitus 20

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young type 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hyperinsulinism due to HNF1A deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• nonpapillary renal cell carcinoma

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Specifications for HNF1A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.871C>T	p.Pro291Ser	missense	Exon 4 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.871C>T	p.Pro291Ser	missense	Exon 4 of 10	NP_001293108.2	F5H0K0
	HNF1A	NM_001406915.1		c.871C>T	p.Pro291Ser	missense	Exon 4 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.871C>T	p.Pro291Ser	missense	Exon 4 of 10	ENSP00000257555.5	P20823-1
	HNF1A	ENST00000544413.2	TSL:1	c.871C>T	p.Pro291Ser	missense	Exon 4 of 10	ENSP00000438804.1	F5H0K0
	HNF1A	ENST00000538646.5	TSL:1	n.684C>T		non_coding_transcript_exon	Exon 3 of 6	ENSP00000443964.1	P20823-4

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000254 AC: 61 AN: 239706 AF XY: 0.000276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000300

Gnomad ASJ exome AF: 0.00559

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.000341

GnomAD4 exome AF: 0.000136 AC: 198 AN: 1457718 Hom.: 0 Cov.: 35 AF XY: 0.000142 AC XY: 103 AN XY: 724894

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.0000228 AC: 1 AN: 43876

Ashkenazi Jewish (ASJ) AF: 0.00487 AC: 126 AN: 25892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1110428

Other (OTH) AF: 0.000465 AC: 28 AN: 60182

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000346 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000165 AC: 20

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	HNF1A-related disorder (1)
-	-	1	Maturity-onset diabetes of the young (1)
-	-	1	Maturity-onset diabetes of the young type 3 (1)
-	-	1	Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	5.2
DANN	Benign	0.47
DEOGEN2	Benign	0.38	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.019	T
MetaSVM	Uncertain	-0.27	T
PhyloP100		0.66
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.20	N
REVEL	Uncertain	0.57
Sift	Benign	0.42	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.40
MVP		0.96
MPC		0.12
ClinPred		0.016	T
GERP RS		1.6
gMVP		0.46
Mutation Taster		=5/95	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: rs151256267; hg19: chr12-121432124; COSMIC: COSV105855435; COSMIC: COSV105855435;