chr20-44401297-GGGAGGGC-G

Position:

• chr20-44401297-GGGAGGGC-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000457.6(HNF4A):​c.-66_-60delAGGGCGG variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00101 in 1,608,084 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00097 (7 hom.)
• Consequence: HNF4A NM_000457.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.96

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 20-44401297-GGGAGGGC-G is Benign according to our data. Variant chr20-44401297-GGGAGGGC-G is described in ClinVar as [Likely_benign]. Clinvar id is 1302796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00144 (219/152298) while in subpopulation NFE AF= 0.000809 (55/68026). AF 95% confidence interval is 0.000638. There are 1 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 219 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF4A	NM_175914.5	c.50-4751_50-4745delAGGGCGG		intron_variant		ENST00000316673.9	NP_787110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF4A	ENST00000316673.9	c.50-4751_50-4745delAGGGCGG		intron_variant		1	NM_175914.5	ENSP00000315180.4

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152178 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000966 AC: 1406 AN: 1455786 Hom.: 7 AF XY: 0.000981 AC XY: 710 AN XY: 723994

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0180

Gnomad4 NFE exome AF: 0.000383

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152298 Hom.: 1 Cov.: 31 AF XY: 0.00207 AC XY: 154 AN XY: 74458

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0149

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00265 Hom.: 0

Bravo AF: 0.000230

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2021	This variant is associated with the following publications: (PMID: 30663027, 27535533, 10768098) -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 06, 2020

The c.-178_-172delAGGGCGG variant in HNF4A is classified as likely benign because it has been identified in 1.6% (55/3472) of Finnish and in 0.3%(45/15410) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP criteria applied: BS1. -

HNF4A-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs555295035; hg19: chr20-43029937;