16-21652594-C-T

Position:

• chr16-21652594-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_005849.4(IGSF6):​c.5G>A​(p.Gly2Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,332 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: IGSF6 NM_005849.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.453

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060837805).
• BP6: Variant 16-21652594-C-T is Benign according to our data. Variant chr16-21652594-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2602634.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGSF6	NM_005849.4	c.5G>A	p.Gly2Glu	missense_variant	1/6	ENST00000268389.6
METTL9	NM_016025.5	c.752-2633C>T		intron_variant		ENST00000358154.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGSF6	ENST00000268389.6	c.5G>A	p.Gly2Glu	missense_variant	1/6	1	NM_005849.4	P1
METTL9	ENST00000358154.8	c.752-2633C>T		intron_variant		1	NM_016025.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456332 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724314

Gnomad4 AFR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.2
DANN	Benign	0.85
DEOGEN2	Benign	0.011	T;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.0031	N
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.061	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.46	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.13	N;N
REVEL	Benign	0.11
Sift	Benign	0.78	T;T
Sift4G	Benign	0.89	T;T
Polyphen		0.0	B;.
Vest4		0.031
MutPred		0.20		Gain of solvent accessibility (P = 0.024);Gain of solvent accessibility (P = 0.024);
MVP		0.14
MPC		0.21
ClinPred		0.026	T
GERP RS		0.90
Varity_R		0.029
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-21663915;