chr3-151436826-G-A

Position:

• chr3-151436826-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_178822.5(IGSF10):​c.7735C>T​(p.His2579Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00684 in 1,614,104 control chromosomes in the GnomAD database, including 602 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.036 (325 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (277 hom.)
• Consequence: IGSF10 NM_178822.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.627

Genes affected

IGSF10 (HGNC:26384): (immunoglobulin superfamily member 10) Predicted to be involved in regulation of neuron migration. Predicted to act upstream of or within ossification. Located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

MED12L (HGNC:16050): (mediator complex subunit 12L) The protein encoded by this gene is part of the Mediator complex, which is involved in transcriptional coactivation of nearly all RNA polymerase II-dependent genes. The Mediator complex links gene-specific transcriptional activators with the basal transcription machinery. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001851201).
• BP6: Variant 3-151436826-G-A is Benign according to our data. Variant chr3-151436826-G-A is described in ClinVar as [Benign]. Clinvar id is 1614226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGSF10	NM_178822.5	c.7735C>T	p.His2579Tyr	missense_variant	8/8	ENST00000282466.4	NP_849144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGSF10	ENST00000282466.4	c.7735C>T	p.His2579Tyr	missense_variant	8/8	1	NM_178822.5	ENSP00000282466.3

Frequencies

GnomAD3 genomes AF: 0.0355 AC: 5409 AN: 152160 Hom.: 323 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.00969 AC: 2436 AN: 251408 Hom.: 138 AF XY: 0.00674 AC XY: 916 AN XY: 135882

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.00807

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00384 AC: 5610 AN: 1461826 Hom.: 277 Cov.: 30 AF XY: 0.00337 AC XY: 2452 AN XY: 727226

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.00899

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.00896

GnomAD4 genome AF: 0.0356 AC: 5423 AN: 152278 Hom.: 325 Cov.: 32 AF XY: 0.0333 AC XY: 2483 AN XY: 74470

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.00821 Hom.: 94

Bravo AF: 0.0411

ESP6500AA AF: 0.123 AC: 544

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0114 AC: 1383

Asia WGS AF: 0.00693 AC: 25 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

IGSF10-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.83
DANN	Benign	0.52
DEOGEN2	Benign	0.00055	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.57	N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.029
MPC		0.023
ClinPred		0.0055	T
GERP RS		-0.63
Varity_R		0.040
gMVP		0.20

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

Other links and lift over

dbSNP: rs7624011; hg19: chr3-151154614;