17-55721027-G-A

Position:

• chr17-55721027-G-A

Variant summary

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

The NM_018286.3(TMEM100):​c.44C>T​(p.Ala15Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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: 6.8e-7 (0 hom.)
• Consequence: TMEM100 NM_018286.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98

Genes affected

TMEM100 (HGNC:25607): (transmembrane protein 100) Involved in BMP signaling pathway. Located in several cellular components, including endoplasmic reticulum; perikaryon; and perinuclear region of cytoplasm. [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=0.055119336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM100	NM_018286.3	c.44C>T	p.Ala15Val	missense_variant	2/2	ENST00000424486.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM100	ENST00000424486.3	c.44C>T	p.Ala15Val	missense_variant	2/2	1	NM_018286.3	P1
TMEM100	ENST00000575734.5	c.44C>T	p.Ala15Val	missense_variant	4/4	2		P1
TMEM100	ENST00000571679.1	c.44C>T	p.Ala15Val	missense_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461500 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727048

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

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

Mar 06, 2023

The c.44C>T (p.A15V) alteration is located in exon 4 (coding exon 1) of the TMEM100 gene. This alteration results from a C to T substitution at nucleotide position 44, causing the alanine (A) at amino acid position 15 to be replaced by a valine (V). 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	0.073
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.36	N
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.055	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.37	N;.;.
REVEL	Benign	0.063
Sift	Benign	0.26	T;.;.
Sift4G	Benign	0.44	T;T;.
Polyphen		0.034	B;B;.
Vest4		0.038
MVP		0.014
MPC		0.25
ClinPred		0.22	T
GERP RS		4.9
Varity_R		0.048
gMVP		0.45

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: rs1373356870; hg19: chr17-53798388;