Genetic Variant C6orf132:p.Thr727Ala (chr6-42105733-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001164446.3(C6orf132):c.2179A>G(p.Thr727Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,536,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

C6orf132
NM_001164446.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.901

Variant links:

Genes affected

C6orf132 (HGNC:21288): (chromosome 6 open reading frame 132)

C6orf132 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018754512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C6orf132	NM_001164446.3 link	c.2179A>G	p.Thr727Ala	missense_variant	Exon 4 of 5	ENST00000341865.9	NP_001157918.1	Q5T0Z8-1
C6orf132	XM_047419258.1 link	c.1624A>G	p.Thr542Ala	missense_variant	Exon 3 of 4		XP_047275214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
C6orf132	ENST00000341865.9 link	c.2179A>G	p.Thr727Ala	missense_variant	Exon 4 of 5	5	NM_001164446.3	ENSP00000341368.4	Q5T0Z8-1
C6orf132	ENST00000696229.1 link	n.*2791A>G		non_coding_transcript_exon_variant	Exon 5 of 6			ENSP00000512495.1	Q5T0Z8-2
C6orf132	ENST00000696229.1 link	n.*2791A>G		3_prime_UTR_variant	Exon 5 of 6			ENSP00000512495.1	Q5T0Z8-2

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

151892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000532

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:

0.00

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000352

AC:

AN:

141926

Hom.:

AF XY:

0.0000264

AC XY:

AN XY:

75892

show subpopulations

Gnomad AFR exome

AF:

0.000658

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1384944

Hom.:

Cov.:

AF XY:

0.0000146

AC XY:

AN XY:

683400

show subpopulations

Gnomad4 AFR exome

AF:

0.000506

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.27e-7

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.000151

AC:

AN:

151892

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74170

show subpopulations

Gnomad4 AFR

AF:

0.000532

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000144

ESP6500AA

AF:

0.00145

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000895

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2179A>G (p.T727A) alteration is located in exon 4 (coding exon 4) of the C6orf132 gene. This alteration results from a A to G substitution at nucleotide position 2179, causing the threonine (T) at amino acid position 727 to be replaced by an alanine (A). 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

0.067

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.54

DEOGEN2

Benign

0.0044

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0083

LIST_S2

Benign

0.18

M_CAP

Benign

0.011

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.34

PROVEAN

Benign

-0.80

REVEL

Benign

0.012

Sift

Benign

0.10

Sift4G

Benign

0.82

Vest4

0.018

MVP

0.014

ClinPred

0.016

GERP RS

-0.62

Varity_R

0.032

gMVP

0.087

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over