rs35029887

Variant names:

• chr1-108922543-ACTT-A
• rs35029887
• NM_013296.5:c.1572_1574delTTC

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_013296.5(GPSM2):​c.1572_1574delTTC​(p.Ser525del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 1,607,800 control chromosomes in the GnomAD database, including 72,591 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11187 hom., cov: 0)
  • Exomes 𝑓: 0.28 (61404 hom.)
• Consequence: GPSM2 NM_013296.5 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.78
• Publications: 18 publications found

Genes affected

GPSM2 (HGNC:29501): (G protein signaling modulator 2) The protein encoded by this gene belongs to a family of proteins that modulate activation of G proteins, which transduce extracellular signals received by cell surface receptors into integrated cellular responses. The N-terminal half of this protein contains 10 copies of leu-gly-asn (LGN) repeat, and the C-terminal half contains 4 GoLoco motifs, which are involved in guanine nucleotide exchange. This protein may play a role in neuroblast division and in the development of normal hearing. Mutations in this gene are associated with autosomal recessive nonsyndromic deafness (DFNB82). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

CLCC1 (HGNC:29675): (chloride channel CLIC like 1) Predicted to enable chloride channel activity. Predicted to be involved in chloride transport. Located in endoplasmic reticulum and mitochondria-associated endoplasmic reticulum membrane. Implicated in retinitis pigmentosa 32. [provided by Alliance of Genome Resources, Apr 2022]

AKNAD1 (HGNC:28398): (AKNA domain containing 1) This gene encodes a protein which contains a domain found in an AT-hook-containing transcription factor. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_013296.5. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 1-108922543-ACTT-A is Benign according to our data. Variant chr1-108922543-ACTT-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013296.5. 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
	GPSM2	NM_013296.5	MANE Select	c.1572_1574delTTC	p.Ser525del	disruptive_inframe_deletion	Exon 13 of 15	NP_037428.3
	GPSM2	NM_001321038.2		c.1572_1574delTTC	p.Ser525del	disruptive_inframe_deletion	Exon 13 of 15	NP_001307967.1	P81274
	GPSM2	NM_001321039.3		c.1572_1574delTTC	p.Ser525del	disruptive_inframe_deletion	Exon 13 of 16	NP_001307968.1	P81274

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPSM2	ENST00000264126.9	TSL:1 MANE Select	c.1572_1574delTTC	p.Ser525del	disruptive_inframe_deletion	Exon 13 of 15	ENSP00000264126.3	P81274
	GPSM2	ENST00000674914.1		c.1623_1625delTTC	p.Ser542del	disruptive_inframe_deletion	Exon 14 of 16	ENSP00000501579.1	A0A6Q8PF02
	GPSM2	ENST00000675087.1		c.1623_1625delTTC	p.Ser542del	disruptive_inframe_deletion	Exon 15 of 17	ENSP00000502020.1	A0A6Q8PF02

Frequencies

GnomAD3 genomes AF: 0.356 AC: 53959 AN: 151478 Hom.: 11154 Cov.: 0

Gnomad AFR AF: 0.570

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.0541

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.290

Gnomad OTH AF: 0.315

GnomAD2 exomes AF: 0.283 AC: 71035 AN: 251372 AF XY: 0.280

Gnomad AFR exome AF: 0.577

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.349

Gnomad EAS exome AF: 0.0575

Gnomad FIN exome AF: 0.305

Gnomad NFE exome AF: 0.287

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.282 AC: 410970 AN: 1456204 Hom.: 61404 AF XY: 0.282 AC XY: 204431 AN XY: 724626

African (AFR) AF: 0.577 AC: 19202 AN: 33306

American (AMR) AF: 0.230 AC: 10269 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 9111 AN: 26088

East Asian (EAS) AF: 0.0560 AC: 2218 AN: 39604

South Asian (SAS) AF: 0.267 AC: 22964 AN: 86132

European-Finnish (FIN) AF: 0.306 AC: 16348 AN: 53400

Middle Eastern (MID) AF: 0.307 AC: 1766 AN: 5754

European-Non Finnish (NFE) AF: 0.282 AC: 311879 AN: 1107004

Other (OTH) AF: 0.286 AC: 17213 AN: 60196

GnomAD4 genome AF: 0.357 AC: 54050 AN: 151596 Hom.: 11187 Cov.: 0 AF XY: 0.351 AC XY: 26030 AN XY: 74088

African (AFR) AF: 0.571 AC: 23533 AN: 41242

American (AMR) AF: 0.250 AC: 3804 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1216 AN: 3460

East Asian (EAS) AF: 0.0541 AC: 279 AN: 5160

South Asian (SAS) AF: 0.251 AC: 1206 AN: 4812

European-Finnish (FIN) AF: 0.308 AC: 3238 AN: 10502

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.290 AC: 19696 AN: 67878

Other (OTH) AF: 0.316 AC: 667 AN: 2110

Alfa AF: 0.332 Hom.: 1621

Bravo AF: 0.360

Asia WGS AF: 0.208 AC: 726 AN: 3478

EpiCase AF: 0.293

EpiControl AF: 0.283

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Chudley-McCullough syndrome (1)
-	-	1	Hearing loss, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=80/20	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs35029887; hg19: chr1-109465165; COSMIC: COSV51442098;