NM_175914.5:c.*1132C>T

Variant names:

• chr20-44430797-C-T
• rs6130615
• NM_175914.5:c.*1132C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_175914.5(HNF4A):​c.*1132C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 152,172 control chromosomes in the GnomAD database, including 6,867 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6859 hom., cov: 30)
  • Exomes 𝑓: 0.15 (8 hom.)
• Consequence: HNF4A NM_175914.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.919
• Publications: 20 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 20-44430797-C-T is Benign according to our data. Variant chr20-44430797-C-T is described in ClinVar as Benign. ClinVar VariationId is 338458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175914.5. 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
	HNF4A	NM_175914.5	MANE Select	c.*1132C>T		3_prime_UTR	Exon 10 of 10	NP_787110.2
	HNF4A	NM_000457.6		c.*1132C>T		3_prime_UTR	Exon 10 of 10	NP_000448.3
	HNF4A	NM_001258355.2		c.*1132C>T		3_prime_UTR	Exon 11 of 11	NP_001245284.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.*1132C>T		3_prime_UTR	Exon 10 of 10	ENSP00000315180.4	P41235-5
	HNF4A	ENST00000316099.10	TSL:1	c.*1132C>T		3_prime_UTR	Exon 10 of 10	ENSP00000312987.3	P41235-1
	HNF4A	ENST00000372920.1	TSL:1	n.*2324C>T		non_coding_transcript_exon	Exon 11 of 11	ENSP00000362011.1	F8WBS7

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37975 AN: 151622 Hom.: 6833 Cov.: 30

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.0978

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.595

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.0959

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.224

GnomAD4 exome AF: 0.153 AC: 66 AN: 432 Hom.: 8 Cov.: 0 AF XY: 0.167 AC XY: 47 AN XY: 282

African (AFR) AF: 0.750 AC: 3 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.214 AC: 18 AN: 84

South Asian (SAS) AF: 1.00 AC: 2 AN: 2

European-Finnish (FIN) AF: 0.100 AC: 9 AN: 90

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.113 AC: 24 AN: 212

Other (OTH) AF: 0.278 AC: 10 AN: 36

GnomAD4 genome AF: 0.251 AC: 38046 AN: 151740 Hom.: 6859 Cov.: 30 AF XY: 0.254 AC XY: 18837 AN XY: 74154

African (AFR) AF: 0.454 AC: 18772 AN: 41326

American (AMR) AF: 0.318 AC: 4850 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 421 AN: 3460

East Asian (EAS) AF: 0.596 AC: 3058 AN: 5134

South Asian (SAS) AF: 0.289 AC: 1383 AN: 4786

European-Finnish (FIN) AF: 0.0959 AC: 1014 AN: 10570

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7945 AN: 67906

Other (OTH) AF: 0.231 AC: 487 AN: 2106

Alfa AF: 0.181 Hom.: 8578

Bravo AF: 0.277

Asia WGS AF: 0.444 AC: 1541 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Familial hyperinsulinism (1)
-	-	1	Maturity-onset diabetes of the young type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.4
DANN	Benign	0.68
PhyloP100		-0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	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: rs6130615; hg19: chr20-43059437;