16-21641562-C-A

Position:

• chr16-21641562-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005849.4(IGSF6):​c.698G>T​(p.Arg233Ile) 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. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IGSF6 NM_005849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.590

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGSF6	NM_005849.4	c.698G>T	p.Arg233Ile	missense_variant	6/6	ENST00000268389.6
METTL9	NM_016025.5	c.752-13665C>A		intron_variant		ENST00000358154.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGSF6	ENST00000268389.6	c.698G>T	p.Arg233Ile	missense_variant	6/6	1	NM_005849.4	P1
METTL9	ENST00000358154.8	c.752-13665C>A		intron_variant		1	NM_016025.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2022

The c.698G>T (p.R233I) alteration is located in exon 6 (coding exon 6) of the IGSF6 gene. This alteration results from a G to T substitution at nucleotide position 698, causing the arginine (R) at amino acid position 233 to be replaced by an isoleucine (I). 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	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.086	N
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.048
Sift	Uncertain	0.025	D
Sift4G	Benign	0.15	T
Polyphen		0.77	P
Vest4		0.26
MutPred		0.29		Loss of MoRF binding (P = 0.0016);
MVP		0.18
MPC		0.49
ClinPred		0.32	T
GERP RS		1.6
Varity_R		0.088
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: 31

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: chr16-21652883;