chr6-108051004-G-C

Variant names:

• chr6-108051004-G-C
• rs3757302
• NM_014028.4:c.783+27C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014028.4(OSTM1):​c.783+27C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.031 in 1,557,642 control chromosomes in the GnomAD database, including 1,635 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.068 (680 hom., cov: 32)
  • Exomes 𝑓: 0.027 (955 hom.)
• Consequence: OSTM1 NM_014028.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.595
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-108051004-G-C is Benign according to our data. Variant chr6-108051004-G-C is described in ClinVar as Benign. ClinVar VariationId is 1253226.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 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.783+27C>G		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.783+27C>G		intron	N/A	ENSP00000193322.3	Q86WC4
	OSTM1	ENST00000492130.2	TSL:1	n.783+27C>G		intron	N/A	ENSP00000514453.1	Q86WC4
	OSTM1	ENST00000699577.1		c.783+27C>G		intron	N/A	ENSP00000514450.1	A0A8V8TPT7

Frequencies

GnomAD3 genomes AF: 0.0676 AC: 10282 AN: 151996 Hom.: 672 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0413

Gnomad ASJ AF: 0.0374

Gnomad EAS AF: 0.0492

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0301

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0532

GnomAD2 exomes AF: 0.0336 AC: 8427 AN: 250852 AF XY: 0.0294

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0353

Gnomad EAS exome AF: 0.0491

Gnomad FIN exome AF: 0.0279

Gnomad NFE exome AF: 0.0243

Gnomad OTH exome AF: 0.0297

GnomAD4 exome AF: 0.0271 AC: 38021 AN: 1405528 Hom.: 955 Cov.: 25 AF XY: 0.0259 AC XY: 18218 AN XY: 702586

African (AFR) AF: 0.179 AC: 5796 AN: 32292

American (AMR) AF: 0.0214 AC: 955 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 839 AN: 25784

East Asian (EAS) AF: 0.0380 AC: 1493 AN: 39312

South Asian (SAS) AF: 0.00420 AC: 358 AN: 85198

European-Finnish (FIN) AF: 0.0276 AC: 1453 AN: 52720

Middle Eastern (MID) AF: 0.0132 AC: 74 AN: 5602

European-Non Finnish (NFE) AF: 0.0236 AC: 25043 AN: 1061394

Other (OTH) AF: 0.0343 AC: 2010 AN: 58568

GnomAD4 genome AF: 0.0678 AC: 10320 AN: 152114 Hom.: 680 Cov.: 32 AF XY: 0.0671 AC XY: 4989 AN XY: 74368

African (AFR) AF: 0.174 AC: 7203 AN: 41480

American (AMR) AF: 0.0412 AC: 630 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0374 AC: 130 AN: 3472

East Asian (EAS) AF: 0.0490 AC: 254 AN: 5186

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4820

European-Finnish (FIN) AF: 0.0301 AC: 318 AN: 10574

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0240 AC: 1630 AN: 67988

Other (OTH) AF: 0.0521 AC: 110 AN: 2110

Alfa AF: 0.0436 Hom.: 73

Bravo AF: 0.0737

Asia WGS AF: 0.0280 AC: 98 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.055
DANN	Benign	0.70
PhyloP100		-0.59
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: rs3757302; hg19: chr6-108372208;