Genetic Variant GOLGA6L6:p.Ile595Val (chr15-20534651-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001145004.2(GOLGA6L6):c.1783A>G(p.Ile595Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 121,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I595L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000016 ( 0 hom., cov: 29)

Exomes 𝑓: 9.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GOLGA6L6
NM_001145004.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.79

Publications

1 publications found

Variant links:

Genes affected

GOLGA6L6 (HGNC:37225): (golgin A6 family like 6)

GOLGA6L6 links:

ENSG00000294965 (HGNC:):

ENSG00000294965 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07904521).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GOLGA6L6	NM_001145004.2 link	c.1783A>G	p.Ile595Val	missense_variant	Exon 8 of 9	ENST00000619213.1	NP_001138476.2	A8MZA4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GOLGA6L6	ENST00000619213.1 link	c.1783A>G	p.Ile595Val	missense_variant	Exon 8 of 9	5	NM_001145004.2	ENSP00000480376.1		A8MZA4
ENSG00000294965	ENST00000727099.1 link	n.182+3998T>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00000821

AC:

AN:

121840

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000185

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.86e-7

AC:

AN:

1014176

Hom.:

Cov.:

AF XY:

0.00000205

AC XY:

AN XY:

488896

show subpopulations

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

African (AFR)

AF:

0.0000455

AC:

AN:

21966

American (AMR)

AF:

0.00

AC:

AN:

17290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13910

East Asian (EAS)

AF:

0.00

AC:

AN:

10232

South Asian (SAS)

AF:

0.00

AC:

AN:

42478

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28724

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2588

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

838288

Other (OTH)

AF:

0.00

AC:

AN:

38700

⚠️ 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: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000164

AC:

AN:

121938

Hom.:

Cov.:

AF XY:

0.0000335

AC XY:

AN XY:

59670

show subpopulations

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

African (AFR)

AF:

0.0000293

AC:

AN:

34080

American (AMR)

AF:

0.00

AC:

AN:

11892

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2698

East Asian (EAS)

AF:

0.00

AC:

AN:

3698

South Asian (SAS)

AF:

0.00

AC:

AN:

3868

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

250

European-Non Finnish (NFE)

AF:

0.0000185

AC:

AN:

54142

Other (OTH)

AF:

0.00

AC:

AN:

1696

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

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.4

(source)

DANN

Benign

0.27

DEOGEN2

Benign

0.0016

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.092

M_CAP

Benign

0.00072

MetaRNN

Benign

0.079

MetaSVM

Benign

-0.93

PhyloP100

-1.8

PrimateAI

Uncertain

0.57

Sift4G

Benign

0.24

Vest4

0.10

MVP

0.014

ClinPred

0.028

Varity_R

0.040

gMVP

0.0011

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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15-20534651-T-C

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