Variant chr16-21643585-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_005849.4(IGSF6):c.548C>T(p.Pro183Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000305 in 1,606,734 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00023 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

IGSF6
NM_005849.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.678

Variant links:

Genes affected

IGSF6 (HGNC:5953): (immunoglobulin superfamily member 6) Predicted to enable transmembrane signaling receptor activity. Predicted to be involved in cell surface receptor signaling pathway and immune response. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

IGSF6 links:

METTL9 (HGNC:24586): (methyltransferase 9, His-X-His N1(pi)-histidine) Enables protein-L-histidine N-pros-methyltransferase activity. Predicted to be involved in methylation. Is active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

METTL9 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=0.018109083).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGSF6	NM_005849.4 linkuse as main transcript	c.548C>T	p.Pro183Leu	missense_variant	4/6	ENST00000268389.6
METTL9	NM_016025.5 linkuse as main transcript	c.752-11642G>A		intron_variant		ENST00000358154.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGSF6	ENST00000268389.6 linkuse as main transcript	c.548C>T	p.Pro183Leu	missense_variant	4/6	1	NM_005849.4	P1
METTL9	ENST00000358154.8 linkuse as main transcript	c.752-11642G>A		intron_variant		1	NM_016025.5	P3	Q9H1A3-1

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

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:

0.00144

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249280

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134768

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000590

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:

0.00000962

AC:

AN:

1454606

Hom.:

Cov.:

AF XY:

0.00000829

AC XY:

AN XY:

724048

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000136

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:

9.04e-7

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000230

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00203

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:

0.00144

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.000465

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

The c.548C>T (p.P183L) alteration is located in exon 4 (coding exon 4) of the IGSF6 gene. This alteration results from a C to T substitution at nucleotide position 548, causing the proline (P) at amino acid position 183 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

0.075

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.70

CADD

Benign

3.2

DANN

Benign

0.48

DEOGEN2

Benign

0.012

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.017

M_CAP

Benign

0.0049

MetaRNN

Benign

0.018

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.61

REVEL

Benign

0.0020

Sift

Benign

0.31

Sift4G

Benign

0.35

Polyphen

0.0040

Vest4

0.18

MutPred

0.23

Loss of glycosylation at P183 (P = 0.0183);

MVP

0.055

MPC

0.16

ClinPred

0.019

GERP RS

-7.6

Varity_R

0.028

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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