rs718174

Variant names:

• chr6-108052051-G-A
• rs718174
• NM_014028.4:c.616-853C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014028.4(OSTM1):​c.616-853C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 151,952 control chromosomes in the GnomAD database, including 14,367 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.41 (14367 hom., cov: 32)
• Consequence: OSTM1 NM_014028.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0270
• Publications: 5 publications found

Genes affected

OSTM1 (HGNC:21652): (osteoclastogenesis associated transmembrane protein 1) This gene encodes a protein that may be involved in the degradation of G proteins via the ubiquitin-dependent proteasome pathway. The encoded protein binds to members of subfamily A of the regulator of the G-protein signaling (RGS) family through an N-terminal leucine-rich region. This protein also has a central RING finger-like domain and E3 ubiquitin ligase activity. This protein is highly conserved from flies to humans. Defects in this gene may cause the autosomal recessive, infantile malignant form of osteopetrosis. [provided by RefSeq, Jul 2008]

OSTM1 Gene-Disease associations (from GenCC):

• autosomal recessive osteopetrosis 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• infantile osteopetrosis with neuroaxonal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014028.4. 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
	OSTM1	NM_014028.4	MANE Select	c.616-853C>T		intron	N/A	NP_054747.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSTM1	ENST00000193322.8	TSL:1 MANE Select	c.616-853C>T		intron	N/A	ENSP00000193322.3	Q86WC4
	OSTM1	ENST00000492130.2	TSL:1	n.616-853C>T		intron	N/A	ENSP00000514453.1	Q86WC4
	OSTM1	ENST00000699577.1		c.616-853C>T		intron	N/A	ENSP00000514450.1	A0A8V8TPT7

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62102 AN: 151834 Hom.: 14331 Cov.: 32

Gnomad AFR AF: 0.597

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.505

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.384

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.409 AC: 62217 AN: 151952 Hom.: 14367 Cov.: 32 AF XY: 0.416 AC XY: 30889 AN XY: 74248

African (AFR) AF: 0.598 AC: 24769 AN: 41444

American (AMR) AF: 0.505 AC: 7719 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 824 AN: 3472

East Asian (EAS) AF: 0.588 AC: 3034 AN: 5158

South Asian (SAS) AF: 0.299 AC: 1444 AN: 4822

European-Finnish (FIN) AF: 0.382 AC: 4027 AN: 10536

Middle Eastern (MID) AF: 0.192 AC: 56 AN: 292

European-Non Finnish (NFE) AF: 0.284 AC: 19265 AN: 67936

Other (OTH) AF: 0.386 AC: 813 AN: 2108

Alfa AF: 0.369 Hom.: 1797

Bravo AF: 0.429

Asia WGS AF: 0.447 AC: 1553 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.2
DANN	Benign	0.47
PhyloP100		-0.027
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs718174; hg19: chr6-108373255; COSMIC: COSV51969218; COSMIC: COSV51969218;