rs4830219

Variant names:

• chrX-131276991-A-G
• rs4830219
• NM_001555.5:c.2556T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001555.5(IGSF1):​c.2556T>C​(p.Tyr852Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 1,208,294 control chromosomes in the GnomAD database, including 46,618 homozygotes. There are 126,236 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (5265 hom., 10858 hem., cov: 22)
  • Exomes 𝑓: 0.32 (41353 hom. 115378 hem.)
• Consequence: IGSF1 NM_001555.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0130
• Publications: 8 publications found

Genes affected

IGSF1 (HGNC:5948): (immunoglobulin superfamily member 1) This gene encodes a member of the immunoglobulin-like domain-containing superfamily. Proteins in this superfamily contain varying numbers of immunoglobulin-like domains and are thought to participate in the regulation of interactions between cells. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

IGSF1 Gene-Disease associations (from GenCC):

• X-linked central congenital hypothyroidism with late-onset testicular enlargement

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000287806 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant X-131276991-A-G is Benign according to our data. Variant chrX-131276991-A-G is described in ClinVar as Benign. ClinVar VariationId is 257591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.013 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001555.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGSF1	NM_001555.5	MANE Select	c.2556T>C	p.Tyr852Tyr	synonymous	Exon 14 of 20	NP_001546.2
	IGSF1	NM_001170961.2		c.2571T>C	p.Tyr857Tyr	synonymous	Exon 14 of 20	NP_001164432.1	Q8N6C5-4
	IGSF1	NM_001438811.1		c.2571T>C	p.Tyr857Tyr	synonymous	Exon 15 of 21	NP_001425740.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGSF1	ENST00000361420.8	TSL:1 MANE Select	c.2556T>C	p.Tyr852Tyr	synonymous	Exon 14 of 20	ENSP00000355010.3	Q8N6C5-1
	IGSF1	ENST00000370903.8	TSL:1	c.2571T>C	p.Tyr857Tyr	synonymous	Exon 14 of 20	ENSP00000359940.3	Q8N6C5-4
	IGSF1	ENST00000370910.5	TSL:1	c.2529T>C	p.Tyr843Tyr	synonymous	Exon 13 of 19	ENSP00000359947.1	Q8N6C5-2

Frequencies

GnomAD3 genomes AF: 0.351 AC: 38727 AN: 110427 Hom.: 5257 Cov.: 22

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.00254

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.349

GnomAD2 exomes AF: 0.297 AC: 54468 AN: 183220 AF XY: 0.289

Gnomad AFR exome AF: 0.429

Gnomad AMR exome AF: 0.301

Gnomad ASJ exome AF: 0.360

Gnomad EAS exome AF: 0.00137

Gnomad FIN exome AF: 0.344

Gnomad NFE exome AF: 0.345

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.325 AC: 356259 AN: 1097814 Hom.: 41353 Cov.: 32 AF XY: 0.318 AC XY: 115378 AN XY: 363264

African (AFR) AF: 0.430 AC: 11350 AN: 26395

American (AMR) AF: 0.303 AC: 10665 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 7004 AN: 19382

East Asian (EAS) AF: 0.00238 AC: 72 AN: 30205

South Asian (SAS) AF: 0.156 AC: 8439 AN: 54141

European-Finnish (FIN) AF: 0.345 AC: 14001 AN: 40525

Middle Eastern (MID) AF: 0.320 AC: 1321 AN: 4132

European-Non Finnish (NFE) AF: 0.343 AC: 288888 AN: 841751

Other (OTH) AF: 0.315 AC: 14519 AN: 46080

GnomAD4 genome AF: 0.351 AC: 38767 AN: 110480 Hom.: 5265 Cov.: 22 AF XY: 0.331 AC XY: 10858 AN XY: 32756

African (AFR) AF: 0.426 AC: 12883 AN: 30257

American (AMR) AF: 0.340 AC: 3545 AN: 10412

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 893 AN: 2627

East Asian (EAS) AF: 0.00283 AC: 10 AN: 3531

South Asian (SAS) AF: 0.123 AC: 318 AN: 2580

European-Finnish (FIN) AF: 0.321 AC: 1901 AN: 5913

Middle Eastern (MID) AF: 0.280 AC: 60 AN: 214

European-Non Finnish (NFE) AF: 0.348 AC: 18388 AN: 52766

Other (OTH) AF: 0.347 AC: 523 AN: 1506

Alfa AF: 0.346 Hom.: 30351

Bravo AF: 0.358

EpiCase AF: 0.347

EpiControl AF: 0.346

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	X-linked central congenital hypothyroidism with late-onset testicular enlargement (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	4.9
DANN	Benign	0.24
PhyloP100		0.013
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4830219; hg19: chrX-130410965; COSMIC: COSV63836051; COSMIC: COSV63836051;