1-32075037-A-T

Variant names:

• chr1-32075037-A-T
• rs764757363
• NM_018056.4:c.91A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018056.4(TMEM39B):​c.91A>T​(p.Thr31Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000193 in 1,551,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T31A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM39B NM_018056.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 1 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025625497).

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.91A>T	p.Thr31Ser	missense	Exon 2 of 9	NP_060526.2	Q9GZU3-1
	TMEM39B	NM_001319677.2		c.-291A>T		5_prime_UTR	Exon 2 of 9	NP_001306606.1	Q9NW51
	TMEM39B	NM_001319678.2		c.-271A>T		5_prime_UTR	Exon 2 of 7	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.91A>T	p.Thr31Ser	missense	Exon 2 of 9	ENSP00000338165.5	Q9GZU3-1
	TMEM39B	ENST00000441402.5	TSL:1	n.91A>T		non_coding_transcript_exon	Exon 2 of 7	ENSP00000390889.1	F8WB89
	TMEM39B	ENST00000969125.1		c.91A>T	p.Thr31Ser	missense	Exon 2 of 10	ENSP00000639184.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399270 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 690162

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

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35726

South Asian (SAS) AF: 0.00 AC: 0 AN: 79222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078908

Other (OTH) AF: 0.00 AC: 0 AN: 58000

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.1
DANN	Benign	0.90
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N
PhyloP100		1.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.11
Sift	Benign	0.76	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.17		Loss of glycosylation at S29 (P = 0.1426)
MVP		0.11
MPC		0.43
ClinPred		0.067	T
GERP RS		-0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.14
Mutation Taster		=295/5	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: rs764757363; hg19: chr1-32540638;