chr22-38247946-C-T

Position:

• chr22-38247946-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012264.5(TMEM184B):​c.16G>A​(p.Asp6Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,431,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TMEM184B NM_012264.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06

Genes affected

TMEM184B (HGNC:1310): (transmembrane protein 184B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057963192).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM184B	NM_012264.5	c.16G>A	p.Asp6Asn	missense_variant	2/9	ENST00000361906.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM184B	ENST00000361906.8	c.16G>A	p.Asp6Asn	missense_variant	2/9	1	NM_012264.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1431580 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 710654

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: 0.0000361

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 33

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

Apr 20, 2024

The c.16G>A (p.D6N) alteration is located in exon 2 (coding exon 1) of the TMEM184B gene. This alteration results from a G to A substitution at nucleotide position 16, causing the aspartic acid (D) at amino acid position 6 to be replaced by an asparagine (N). 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	Benign	0.087
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.58	.;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.58	N;N
REVEL	Benign	0.077
Sift	Benign	0.074	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.0	B;B
Vest4		0.21
MutPred		0.13		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.043
MPC		0.52
ClinPred		0.45	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.32

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: rs1356759365; hg19: chr22-38643952;