Genetic Variant R3HDML-AS1:n.3A>G (chr20-44355240-T-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NR_184036.1(R3HDML-AS1):n.3A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0008 in 164,932 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00080 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00079 ( 0 hom. )

Consequence

R3HDML-AS1
NR_184036.1 non_coding_transcript_exon

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.0690

Publications

0 publications found

Variant links:

Genes affected

R3HDML-AS1 (HGNC:55830): (R3HDML antisense RNA 1)

R3HDML-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 20-44355240-T-C is Benign according to our data. Variant chr20-44355240-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435430.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
R3HDML-AS1	NR_184036.1 link	n.3A>G		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
R3HDML-AS1	ENST00000735551.1 link	n.160-101A>G		intron_variant	Intron 1 of 4
R3HDML-AS1	ENST00000438702.1 link	n.-55A>G		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00549

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00141

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.000790

AC:

AN:

12660

Hom.:

AF XY:

0.00117

AC XY:

AN XY:

6822

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

114

American (AMR)

AF:

0.000643

AC:

AN:

3110

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

736

South Asian (SAS)

AF:

0.00

AC:

AN:

2194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00138

AC:

AN:

5816

Other (OTH)

AF:

0.00

AC:

AN:

510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000801

AC:

122

AN:

152272

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41540

American (AMR)

AF:

0.000523

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00141

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000157

Hom.:

Bravo

AF:

0.000854

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 31, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Maturity onset diabetes mellitus in young

Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs377144780 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

4.6

(source)

DANN

Benign

0.68

PhyloP100

0.069

PromoterAI

-0.0019

Neutral

(source)

Splicing

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

Publications

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20-44355240-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over