6-108042421-T-C

Variant names:

• chr6-108042421-T-C
• rs60621815
• NM_014028.4:c.*2364A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014028.4(OSTM1):​c.*2364A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000446 in 103,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OSTM1 NM_014028.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.380
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

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.*2364A>G		3_prime_UTR	Exon 6 of 6	NP_054747.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSTM1	ENST00000193322.8	TSL:1 MANE Select	c.*2364A>G		3_prime_UTR	Exon 6 of 6	ENSP00000193322.3	Q86WC4
	OSTM1	ENST00000492130.2	TSL:1	n.*2218+146A>G		intron	N/A	ENSP00000514453.1	Q86WC4
	OSTM1	ENST00000699577.1		c.*2364A>G		3_prime_UTR	Exon 7 of 7	ENSP00000514450.1	A0A8V8TPT7

Frequencies

GnomAD3 genomes AF: 0.000446 AC: 46 AN: 103176 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000770

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000500

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000508

Gnomad FIN AF: 0.00140

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000172

Gnomad OTH AF: 0.000699

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.000446 AC: 46 AN: 103202 Hom.: 0 Cov.: 26 AF XY: 0.000500 AC XY: 25 AN XY: 50002

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000769 AC: 22 AN: 28616

American (AMR) AF: 0.000499 AC: 5 AN: 10028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2684

East Asian (EAS) AF: 0.00 AC: 0 AN: 3486

South Asian (SAS) AF: 0.000510 AC: 2 AN: 3922

European-Finnish (FIN) AF: 0.00140 AC: 8 AN: 5710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 250

European-Non Finnish (NFE) AF: 0.000172 AC: 8 AN: 46402

Other (OTH) AF: 0.000693 AC: 1 AN: 1442

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000545236), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive osteopetrosis 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.1
DANN	Benign	0.67
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism

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: rs60621815; hg19: chr6-108363625;