chr1-32077288-C-T

Variant names:

• chr1-32077288-C-T
• NM_018056.4:c.560C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018056.4(TMEM39B):​c.560C>T​(p.Ser187Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TMEM39B NM_018056.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50
• Publications: 0 publications found

Genes affected

TMEM39B (HGNC:25510): (transmembrane protein 39B) Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018056.4. 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
	TMEM39B	NM_018056.4	MANE Select	c.560C>T	p.Ser187Phe	missense	Exon 5 of 9	NP_060526.2	Q9GZU3-1
	TMEM39B	NM_001319677.2		c.179C>T	p.Ser60Phe	missense	Exon 5 of 9	NP_001306606.1	Q9NW51
	TMEM39B	NM_001319678.2		c.-11+1466C>T		intron	N/A	NP_001306607.1	Q9GZU3-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM39B	ENST00000336294.10	TSL:1 MANE Select	c.560C>T	p.Ser187Phe	missense	Exon 5 of 9	ENSP00000338165.5	Q9GZU3-1
	TMEM39B	ENST00000441402.5	TSL:1	n.351+1466C>T		intron	N/A	ENSP00000390889.1	F8WB89
	TMEM39B	ENST00000969125.1		c.560C>T	p.Ser187Phe	missense	Exon 5 of 10	ENSP00000639184.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.44	B
Vest4		0.93
MutPred		0.89		Loss of catalytic residue at S187 (P = 0.075)
MVP		0.46
MPC		1.2
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.60
gMVP		0.93
Mutation Taster		=42/58	disease causing

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

hg19: chr1-32542889;