rs781171810

Variant names:

• chr9-105694746-C-T
• rs781171810
• NM_018112.3:c.86C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-105694746-C-T
• chr9-105694746-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_018112.3(TMEM38B):​c.86C>T​(p.Ser29Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,603,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: TMEM38B NM_018112.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

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.86C>T	p.Ser29Leu	missense	Exon 1 of 6	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.86C>T	p.Ser29Leu	missense	Exon 1 of 6	ENSP00000363824.3	Q9NVV0
	TMEM38B	ENST00000956696.1		c.86C>T	p.Ser29Leu	missense	Exon 1 of 7	ENSP00000626755.1
	TMEM38B	ENST00000884631.1		c.86C>T	p.Ser29Leu	missense	Exon 1 of 6	ENSP00000554690.1

Frequencies

GnomAD3 genomes AF: 0.0000668 AC: 10 AN: 149620 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 249534 AF XY: 0.00000740

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000963 AC: 14 AN: 1453702 Hom.: 0 Cov.: 32 AF XY: 0.00000553 AC XY: 4 AN XY: 723186

African (AFR) AF: 0.0000904 AC: 3 AN: 33172

American (AMR) AF: 0.00 AC: 0 AN: 44398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25822

East Asian (EAS) AF: 0.00 AC: 0 AN: 38992

South Asian (SAS) AF: 0.00 AC: 0 AN: 86096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.00000904 AC: 10 AN: 1106708

Other (OTH) AF: 0.0000167 AC: 1 AN: 59870

GnomAD4 genome AF: 0.0000668 AC: 10 AN: 149620 Hom.: 0 Cov.: 31 AF XY: 0.0000550 AC XY: 4 AN XY: 72744

African (AFR) AF: 0.000197 AC: 8 AN: 40614

American (AMR) AF: 0.00 AC: 0 AN: 14674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5042

South Asian (SAS) AF: 0.00 AC: 0 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67778

Other (OTH) AF: 0.00 AC: 0 AN: 2044

Alfa AF: 0.0000658 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.47		Loss of catalytic residue at S29 (P = 0.0517)
MVP		0.68
MPC		0.23
ClinPred		0.72	D
GERP RS		4.6
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.81
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs781171810; hg19: chr9-108457027;