rs1800961

Variant names:

• chr20-44413724-C-T
• rs1800961
• NM_175914.5:c.350C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000457.6(HNF4A):​c.416C>T​(p.Thr139Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,613,536 control chromosomes in the GnomAD database, including 822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (74 hom., cov: 31)
  • Exomes 𝑓: 0.030 (748 hom.)
• Consequence: HNF4A NM_000457.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 7.87
• Publications: 299 publications found

Genes affected

HNF4A (HGNC:5024): (hepatocyte nuclear factor 4 alpha) The protein encoded by this gene is a nuclear transcription factor which binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes. This gene may play a role in development of the liver, kidney, and intestines. Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type I. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms. [provided by RefSeq, Apr 2012]

HNF4A Gene-Disease associations (from GenCC):

• maturity-onset diabetes of the young type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
• hyperinsulinism due to HNF4A deficiency

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_000457.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0070026815).
• BP6: Variant 20-44413724-C-T is Benign according to our data. Variant chr20-44413724-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0251 (3818/152112) while in subpopulation AMR AF = 0.051 (779/15262). AF 95% confidence interval is 0.0481. There are 74 homozygotes in GnomAd4. There are 1869 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3818 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000457.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	NM_175914.5	MANE Select	c.350C>T	p.Thr117Ile	missense	Exon 4 of 10	NP_787110.2
	HNF4A	NM_000457.6		c.416C>T	p.Thr139Ile	missense	Exon 4 of 10	NP_000448.3
	HNF4A	NM_001258355.2		c.395C>T	p.Thr132Ile	missense	Exon 5 of 11	NP_001245284.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.350C>T	p.Thr117Ile	missense	Exon 4 of 10	ENSP00000315180.4
	HNF4A	ENST00000316099.10	TSL:1	c.416C>T	p.Thr139Ile	missense	Exon 4 of 10	ENSP00000312987.3
	HNF4A	ENST00000415691.2	TSL:1	c.416C>T	p.Thr139Ile	missense	Exon 4 of 10	ENSP00000412111.1

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3815 AN: 151994 Hom.: 72 Cov.: 31

Gnomad AFR AF: 0.00587

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0507

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.0134

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.0416

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0297

Gnomad OTH AF: 0.0216

GnomAD2 exomes AF: 0.0308 AC: 7718 AN: 250866 AF XY: 0.0300

Gnomad AFR exome AF: 0.00530

Gnomad AMR exome AF: 0.0454

Gnomad ASJ exome AF: 0.0273

Gnomad EAS exome AF: 0.0136

Gnomad FIN exome AF: 0.0414

Gnomad NFE exome AF: 0.0322

Gnomad OTH exome AF: 0.0313

GnomAD4 exome AF: 0.0300 AC: 43792 AN: 1461424 Hom.: 748 Cov.: 32 AF XY: 0.0298 AC XY: 21648 AN XY: 727022

African (AFR) AF: 0.00496 AC: 166 AN: 33476

American (AMR) AF: 0.0488 AC: 2181 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 662 AN: 26136

East Asian (EAS) AF: 0.0110 AC: 437 AN: 39692

South Asian (SAS) AF: 0.0256 AC: 2205 AN: 86224

European-Finnish (FIN) AF: 0.0420 AC: 2241 AN: 53398

Middle Eastern (MID) AF: 0.00815 AC: 47 AN: 5766

European-Non Finnish (NFE) AF: 0.0308 AC: 34186 AN: 1111658

Other (OTH) AF: 0.0276 AC: 1667 AN: 60384

GnomAD4 genome AF: 0.0251 AC: 3818 AN: 152112 Hom.: 74 Cov.: 31 AF XY: 0.0251 AC XY: 1869 AN XY: 74344

African (AFR) AF: 0.00585 AC: 243 AN: 41526

American (AMR) AF: 0.0510 AC: 779 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3470

East Asian (EAS) AF: 0.0128 AC: 66 AN: 5140

South Asian (SAS) AF: 0.0284 AC: 137 AN: 4816

European-Finnish (FIN) AF: 0.0416 AC: 440 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0297 AC: 2017 AN: 67998

Other (OTH) AF: 0.0213 AC: 45 AN: 2108

Alfa AF: 0.0283 Hom.: 356

Bravo AF: 0.0245

TwinsUK AF: 0.0283 AC: 105

ALSPAC AF: 0.0267 AC: 103

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.0328 AC: 282

ExAC AF: 0.0310 AC: 3769

Asia WGS AF: 0.0270 AC: 92 AN: 3478

EpiCase AF: 0.0260

EpiControl AF: 0.0262

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Familial hyperinsulinism (1)
-	-	1	Maturity onset diabetes mellitus in young (1)
-	-	1	Maturity-onset diabetes of the young type 1 (1)
-	-	1	Monogenic diabetes (1)
-	-	1	Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.062
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0070	T
MetaSVM	Uncertain	-0.031	T
MutationAssessor	Benign	1.2	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.43
Sift	Benign	0.25	T
Sift4G	Benign	0.20	T
Polyphen		0.0090	B
Vest4		0.34
MPC		0.68
ClinPred		0.028	T
GERP RS		5.2
Varity_R		0.33
gMVP		0.69
Mutation Taster		=80/20	polymorphism (auto)

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: rs1800961; hg19: chr20-43042364; COSMIC: COSV57385393;