1-109092951-C-G

Position:

• chr1-109092951-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020141.4(TMEM167B):​c.72C>G​(p.Phe24Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: TMEM167B NM_020141.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77

Genes affected

TMEM167B (HGNC:30187): (transmembrane protein 167B) Involved in constitutive secretory pathway. Located in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.107682854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM167B	NM_020141.4	c.72C>G	p.Phe24Leu	missense_variant	2/3	ENST00000338272.9	NP_064526.1
TMEM167B	NM_001322248.2	c.72C>G	p.Phe24Leu	missense_variant	2/3		NP_001309177.1
TMEM167B	NR_136242.2	n.270C>G		non_coding_transcript_exon_variant	3/4
TMEM167B	NR_136243.2	n.120-1466C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM167B	ENST00000338272.9	c.72C>G	p.Phe24Leu	missense_variant	2/3	1	NM_020141.4	ENSP00000342148	P1
TMEM167B	ENST00000651489.1	c.72C>G	p.Phe24Leu	missense_variant	2/3			ENSP00000498719
TMEM167B	ENST00000473828.1	n.139C>G		non_coding_transcript_exon_variant	2/2	2
TMEM167B	ENST00000479160.1	n.254C>G		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461888 Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2023

The c.72C>G (p.F24L) alteration is located in exon 2 (coding exon 2) of the TMEM167B gene. This alteration results from a C to G substitution at nucleotide position 72, causing the phenylalanine (F) at amino acid position 24 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.0074	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.081
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.97	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.98	N
REVEL	Benign	0.068
Sift	Benign	0.75	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.32
MutPred		0.44		Loss of methylation at K25 (P = 0.0298);
MVP		0.043
MPC		0.71
ClinPred		0.89	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs766842437; hg19: chr1-109635573;