9-105694855-C-T

Variant names:

• chr9-105694855-C-T
• rs567962441
• NM_018112.3:c.112+83C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_018112.3(TMEM38B):​c.112+83C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 5,918 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (4 hom., cov: 0)
  • Exomes 𝑓: 0.0025 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMEM38B NM_018112.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.915
• Publications: 0 publications found

Genes affected

TMEM38B (HGNC:25535): (transmembrane protein 38B) This gene encodes an intracellular monovalent cation channel that functions in maintenance of intracellular calcium release. Mutations in this gene may be associated with autosomal recessive osteogenesis. [provided by RefSeq, Oct 2012]

TMEM38B Gene-Disease associations (from GenCC):

• osteogenesis imperfecta type 14

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 9-105694855-C-T is Benign according to our data. Variant chr9-105694855-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1200068.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018112.3. 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
	TMEM38B	NM_018112.3	MANE Select	c.112+83C>T		intron	N/A	NP_060582.1	Q9NVV0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM38B	ENST00000374692.8	TSL:1 MANE Select	c.112+83C>T		intron	N/A	ENSP00000363824.3	Q9NVV0
	TMEM38B	ENST00000956696.1		c.112+83C>T		intron	N/A	ENSP00000626755.1
	TMEM38B	ENST00000884631.1		c.112+83C>T		intron	N/A	ENSP00000554690.1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 411 AN: 37966 Hom.: 4 Cov.: 0

Gnomad AFR AF: 0.0386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00514

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000808

Gnomad MID AF: 0.0114

Gnomad NFE AF: 0.000153

Gnomad OTH AF: 0.0172

GnomAD4 exome AF: 0.00253 AC: 15 AN: 5918 Hom.: 0 AF XY: 0.00220 AC XY: 8 AN XY: 3634

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

African (AFR) AF: 0.0778 AC: 7 AN: 90

American (AMR) AF: 0.00368 AC: 1 AN: 272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 232

East Asian (EAS) AF: 0.00 AC: 0 AN: 130

South Asian (SAS) AF: 0.00 AC: 0 AN: 1606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 700

Middle Eastern (MID) AF: 0.0333 AC: 1 AN: 30

European-Non Finnish (NFE) AF: 0.00115 AC: 3 AN: 2604

Other (OTH) AF: 0.0118 AC: 3 AN: 254

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000381930), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0108 AC: 410 AN: 37986 Hom.: 4 Cov.: 0 AF XY: 0.0107 AC XY: 188 AN XY: 17510

African (AFR) AF: 0.0384 AC: 384 AN: 9994

American (AMR) AF: 0.00514 AC: 14 AN: 2726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1028

East Asian (EAS) AF: 0.00 AC: 0 AN: 1648

South Asian (SAS) AF: 0.00 AC: 0 AN: 1002

European-Finnish (FIN) AF: 0.000808 AC: 1 AN: 1238

Middle Eastern (MID) AF: 0.0119 AC: 1 AN: 84

European-Non Finnish (NFE) AF: 0.000153 AC: 3 AN: 19578

Other (OTH) AF: 0.0169 AC: 7 AN: 414

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.00335

ClinVar

ClinVar submissions

Significance: Likely 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	-0.72
CADD	Benign	8.4
DANN	Benign	0.93
PhyloP100		-0.92
PromoterAI		-0.036	Neutral

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: rs567962441; hg19: chr9-108457136;