rs6103731

Variant names:

• chr20-44418653-A-G
• rs6103731
• NM_175914.5:c.670+141A>G

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.670+141A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 653,248 control chromosomes in the GnomAD database, including 102,511 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene HNF4A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.55 (23129 hom., cov: 32)
  • Exomes 𝑓: 0.55 (79382 hom.)
• Consequence: HNF4A NM_175914.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.431
• Publications: 9 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

Specifications for HNF4A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 20-44418653-A-G is Benign according to our data. Variant chr20-44418653-A-G is described in ClinVar as Benign. ClinVar VariationId is 676879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.587 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.670+141A>G		intron	N/A	NP_787110.2
	HNF4A	NM_000457.6		c.736+141A>G		intron	N/A	NP_000448.3
	HNF4A	NM_001258355.2		c.715+141A>G		intron	N/A	NP_001245284.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF4A	ENST00000316673.9	TSL:1 MANE Select	c.670+141A>G		intron	N/A	ENSP00000315180.4	P41235-5
	HNF4A	ENST00000316099.10	TSL:1	c.736+141A>G		intron	N/A	ENSP00000312987.3	P41235-1
	HNF4A	ENST00000415691.2	TSL:1	c.736+141A>G		intron	N/A	ENSP00000412111.1	P41235-2

Frequencies

GnomAD3 genomes AF: 0.547 AC: 83173 AN: 151940 Hom.: 23120 Cov.: 32

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.528

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.592

Gnomad OTH AF: 0.572

GnomAD4 exome AF: 0.554 AC: 277904 AN: 501190 Hom.: 79382 AF XY: 0.552 AC XY: 146613 AN XY: 265428

African (AFR) AF: 0.524 AC: 7462 AN: 14242

American (AMR) AF: 0.442 AC: 11375 AN: 25730

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 10528 AN: 15220

East Asian (EAS) AF: 0.310 AC: 9909 AN: 31948

South Asian (SAS) AF: 0.492 AC: 25564 AN: 52008

European-Finnish (FIN) AF: 0.546 AC: 17240 AN: 31594

Middle Eastern (MID) AF: 0.638 AC: 1374 AN: 2152

European-Non Finnish (NFE) AF: 0.595 AC: 178649 AN: 300308

Other (OTH) AF: 0.565 AC: 15803 AN: 27988

GnomAD4 genome AF: 0.547 AC: 83221 AN: 152058 Hom.: 23129 Cov.: 32 AF XY: 0.541 AC XY: 40217 AN XY: 74326

African (AFR) AF: 0.520 AC: 21544 AN: 41464

American (AMR) AF: 0.499 AC: 7633 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2436 AN: 3470

East Asian (EAS) AF: 0.294 AC: 1522 AN: 5176

South Asian (SAS) AF: 0.479 AC: 2312 AN: 4822

European-Finnish (FIN) AF: 0.528 AC: 5576 AN: 10560

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.592 AC: 40233 AN: 67968

Other (OTH) AF: 0.574 AC: 1210 AN: 2108

Alfa AF: 0.574 Hom.: 37611

Bravo AF: 0.544

Asia WGS AF: 0.404 AC: 1404 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.84
DANN	Benign	0.85
PhyloP100		-0.43
Mutation Taster		=100/0	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: rs6103731; hg19: chr20-43047293; COSMIC: COSV57390557;