Genetic Variant AHI1-DT:n.456A>C (chr6-135689660-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The ENST00000421378.4(AHI1-DT):n.456A>C 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 0.00822 in 151,876 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0082 ( 15 hom., cov: 32)

Exomes 𝑓: 0.015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AHI1-DT
ENST00000421378.4 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.14

Publications

3 publications found

Variant links:

Genes affected

AHI1-DT (HGNC:32526): (AHI1 divergent transcript)

AHI1-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

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

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00822 (1248/151876) while in subpopulation SAS AF = 0.0415 (200/4814). AF 95% confidence interval is 0.0368. There are 15 homozygotes in GnomAd4. There are 652 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
AHI1-DT	NR_026805.1 link	n.458A>C	non_coding_transcript_exon_variant	Exon 4 of 4
AHI1-DT	NR_152842.1 link	n.572A>C	non_coding_transcript_exon_variant	Exon 5 of 6
AHI1-DT	NR_152844.1 link	n.572A>C	non_coding_transcript_exon_variant	Exon 5 of 5
AHI1-DT	NR_152845.1 link	n.696A>C	non_coding_transcript_exon_variant	Exon 5 of 5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
AHI1-DT	ENST00000421378.4 link	n.456A>C	non_coding_transcript_exon_variant	Exon 4 of 4	1
AHI1-DT	ENST00000579944.1 link	n.154A>C	non_coding_transcript_exon_variant	Exon 2 of 3	2
AHI1-DT	ENST00000653664.1 link	n.596A>C	non_coding_transcript_exon_variant	Exon 5 of 5

Frequencies

GnomAD3 genomes

AF:

0.00822

AC:

1248

AN:

151758

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00643

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.00213

Gnomad SAS

AF:

0.0415

Gnomad FIN

AF:

0.00730

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.00670

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0147

AC:

AN:

Hom.:

Cov.:

AF XY:

0.0227

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0185

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00822

AC:

1248

AN:

151876

Hom.:

Cov.:

AF XY:

0.00879

AC XY:

652

AN XY:

74206

show subpopulations

African (AFR)

AF:

0.00174

AC:

AN:

41398

American (AMR)

AF:

0.00643

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

AN:

3470

East Asian (EAS)

AF:

0.00213

AC:

AN:

5158

South Asian (SAS)

AF:

0.0415

AC:

200

AN:

4814

European-Finnish (FIN)

AF:

0.00730

AC:

AN:

10542

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0104

AC:

706

AN:

67926

Other (OTH)

AF:

0.00663

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

120

180

240

300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00189

Hom.:

295

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.17

(source)

DANN

Benign

0.59

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over