15-20534587-G-A

Variant names:

• chr15-20534587-G-A
• rs28590435
• NM_001145004.2:c.1847C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_001145004.2(GOLGA6L6):​c.1847C>T​(p.Thr616Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 97,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0039 (8 hom.)
  • Failed GnomAD Quality Control
• Consequence: GOLGA6L6 NM_001145004.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.18

Genes affected

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PM2: Variant has high frequency in the AFR (0.0403) population. However there is too low homozygotes in high coverage region: (expected more than 22, got 0).
• BP4: Computational evidence support a benign effect (MetaRNN=0.0030660033).
• BP6: Variant 15-20534587-G-A is Benign according to our data. Variant chr15-20534587-G-A is described in ClinVar as [Benign]. Clinvar id is 402906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0302 (2941/97252) while in subpopulation AFR AF = 0.0425 (995/23426). AF 95% confidence interval is 0.0403. There are 0 homozygotes in GnomAd4. There are 1382 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position FAILED quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GOLGA6L6	NM_001145004.2	c.1847C>T	p.Thr616Met	missense_variant	Exon 8 of 9	ENST00000619213.1	NP_001138476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GOLGA6L6	ENST00000619213.1	c.1847C>T	p.Thr616Met	missense_variant	Exon 8 of 9	5	NM_001145004.2	ENSP00000480376.1

Frequencies

GnomAD3 genomes AF: 0.0303 AC: 2945 AN: 97150 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.0115

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.0177

Gnomad EAS AF: 0.00129

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0295

Gnomad MID AF: 0.0362

Gnomad NFE AF: 0.0307

Gnomad OTH AF: 0.0302

GnomAD2 exomes AF: 0.0770 AC: 9379 AN: 121758 AF XY: 0.0779

Gnomad AFR exome AF: 0.0737

Gnomad AMR exome AF: 0.0493

Gnomad ASJ exome AF: 0.0752

Gnomad EAS exome AF: 0.000478

Gnomad FIN exome AF: 0.0749

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.0894

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00387 AC: 4674 AN: 1208304 Hom.: 8 Cov.: 66 AF XY: 0.00376 AC XY: 2242 AN XY: 595844

Gnomad4 AFR exome AF: 0.00965 AC: 255 AN: 26438

Gnomad4 AMR exome AF: 0.00350 AC: 110 AN: 31472

Gnomad4 ASJ exome AF: 0.00273 AC: 58 AN: 21264

Gnomad4 EAS exome AF: 0.0000883 AC: 3 AN: 33988

Gnomad4 SAS exome AF: 0.00125 AC: 91 AN: 72518

Gnomad4 FIN exome AF: 0.00605 AC: 240 AN: 39686

Gnomad4 NFE exome AF: 0.00396 AC: 3690 AN: 931020

Gnomad4 Remaining exome AF: 0.00430 AC: 206 AN: 47852

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0302 AC: 2941 AN: 97252 Hom.: 0 Cov.: 34 AF XY: 0.0290 AC XY: 1382 AN XY: 47672

Gnomad4 AFR AF: 0.0425 AC: 0.0424742 AN: 0.0424742

Gnomad4 AMR AF: 0.0199 AC: 0.0198929 AN: 0.0198929

Gnomad4 ASJ AF: 0.0177 AC: 0.0177469 AN: 0.0177469

Gnomad4 EAS AF: 0.00130 AC: 0.00129735 AN: 0.00129735

Gnomad4 SAS AF: 0.0179 AC: 0.0178571 AN: 0.0178571

Gnomad4 FIN AF: 0.0295 AC: 0.0295409 AN: 0.0295409

Gnomad4 NFE AF: 0.0306 AC: 0.0306461 AN: 0.0306461

Gnomad4 OTH AF: 0.0299 AC: 0.029872 AN: 0.029872

⚠️ The allele balance in gnomAD4 Genomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0570 Hom.: 18

ExAC AF: 0.0675 AC: 1379

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.24
DANN	Benign	0.22
DEOGEN2	Benign	0.00060	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00091	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.56	T
Sift4G	Benign	0.22	T
Vest4		0.035
ClinPred		0.016	T
Varity_R		0.015
gMVP		0.0038
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

Publications

LitVar

Other links and lift over

dbSNP: rs28590435; hg19: chr15-20739825; COSMIC: COSV71180651;