chr15-20534651-T-A

Variant names:

• chr15-20534651-T-A
• rs1291033117
• NM_001145004.2:c.1783A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145004.2(GOLGA6L6):​c.1783A>T​(p.Ile595Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GOLGA6L6 NM_001145004.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.79
• Publications: 0 publications found

Genes affected

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

ENSG00000294965 (HGNC:):

ACMG classification

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=0.07123342).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GOLGA6L6	NM_001145004.2	c.1783A>T	p.Ile595Leu	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.1783A>T	p.Ile595Leu	missense_variant	Exon 8 of 9	5	NM_001145004.2	ENSP00000480376.1
ENSG00000294965	ENST00000727099.1	n.182+3998T>A		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000197 AC: 2 AN: 1014208 Hom.: 0 Cov.: 33 AF XY: 0.00000205 AC XY: 1 AN XY: 488916

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

African (AFR) AF: 0.00 AC: 0 AN: 21966

American (AMR) AF: 0.00 AC: 0 AN: 17294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13912

East Asian (EAS) AF: 0.0000977 AC: 1 AN: 10232

South Asian (SAS) AF: 0.0000235 AC: 1 AN: 42478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2588

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838314

Other (OTH) AF: 0.00 AC: 0 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.

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1861A>T (p.I621L) alteration is located in exon 8 (coding exon 8) of the GOLGA6L6 gene. This alteration results from a A to T substitution at nucleotide position 1861, causing the isoleucine (I) at amino acid position 621 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.5
DANN	Benign	0.43
DEOGEN2	Benign	0.00076	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.10	T
M_CAP	Benign	0.00097	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.90	T
PhyloP100		-1.8
PrimateAI	Uncertain	0.58	T
Sift4G	Benign	1.0	T
Vest4		0.13
MVP		0.014
ClinPred		0.032	T
Varity_R		0.10
gMVP		0.0014

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: rs1291033117; hg19: chr15-20739889;