NM_001145004.2:c.1847C>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

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. 11/16 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
• Publications: 4 publications found

Genes affected

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

ENSG00000294965 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 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.

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
ENSG00000294965	ENST00000727099.1	n.182+3934G>A		intron_variant	Intron 2 of 2

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

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

African (AFR) AF: 0.00965 AC: 255 AN: 26438

American (AMR) AF: 0.00350 AC: 110 AN: 31472

Ashkenazi Jewish (ASJ) AF: 0.00273 AC: 58 AN: 21264

East Asian (EAS) AF: 0.0000883 AC: 3 AN: 33988

South Asian (SAS) AF: 0.00125 AC: 91 AN: 72518

European-Finnish (FIN) AF: 0.00605 AC: 240 AN: 39686

Middle Eastern (MID) AF: 0.00516 AC: 21 AN: 4066

European-Non Finnish (NFE) AF: 0.00396 AC: 3690 AN: 931020

Other (OTH) AF: 0.00430 AC: 206 AN: 47852

⚠️ 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.

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

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

African (AFR) AF: 0.0425 AC: 995 AN: 23426

American (AMR) AF: 0.0199 AC: 208 AN: 10456

Ashkenazi Jewish (ASJ) AF: 0.0177 AC: 46 AN: 2592

East Asian (EAS) AF: 0.00130 AC: 5 AN: 3854

South Asian (SAS) AF: 0.0179 AC: 57 AN: 3192

European-Finnish (FIN) AF: 0.0295 AC: 175 AN: 5924

Middle Eastern (MID) AF: 0.0373 AC: 5 AN: 134

European-Non Finnish (NFE) AF: 0.0306 AC: 1402 AN: 45748

Other (OTH) AF: 0.0299 AC: 42 AN: 1406

⚠️ 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.

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
PhyloP100		-2.2
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

Other links and lift over

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