NM_181719.7:c.1873A>G

Variant names:

• chr1-19683072-T-C
• rs761041338
• NM_181719.7:c.1873A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_181719.7(TMCO4):​c.1873A>G​(p.Lys625Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000483 in 1,449,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TMCO4 NM_181719.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.909
• Publications: 0 publications found

Genes affected

TMCO4 (HGNC:27393): (transmembrane and coiled-coil domains 4) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021545112).
• BP6: Variant 1-19683072-T-C is Benign according to our data. Variant chr1-19683072-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3326588.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181719.7. 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
	TMCO4	NM_181719.7	MANE Select	c.1873A>G	p.Lys625Glu	missense	Exon 16 of 16	NP_859070.3
	TMCO4	NM_001349112.3		c.1873A>G	p.Lys625Glu	missense	Exon 15 of 15	NP_001336041.1	Q5TGY1-1
	TMCO4	NM_001349113.3		c.1873A>G	p.Lys625Glu	missense	Exon 16 of 16	NP_001336042.1	Q5TGY1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCO4	ENST00000294543.11	TSL:1 MANE Select	c.1873A>G	p.Lys625Glu	missense	Exon 16 of 16	ENSP00000294543.6	Q5TGY1-1
	TMCO4	ENST00000375127.5	TSL:1	c.1657+216A>G		intron	N/A	ENSP00000364269.1	A0A075B6H3
	TMCO4	ENST00000866952.1		c.1873A>G	p.Lys625Glu	missense	Exon 18 of 18	ENSP00000537011.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000168 AC: 4 AN: 238612 AF XY: 0.0000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000483 AC: 7 AN: 1449476 Hom.: 0 Cov.: 30 AF XY: 0.00000417 AC XY: 3 AN XY: 720282

African (AFR) AF: 0.00 AC: 0 AN: 33176

American (AMR) AF: 0.000116 AC: 5 AN: 43164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24930

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 84052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52650

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5680

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106438

Other (OTH) AF: 0.00 AC: 0 AN: 59762

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Likely benign

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	Benign	0.058
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.2
DANN	Benign	0.53
DEOGEN2	Benign	0.00015	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-0.91
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.0050
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.035
MutPred		0.27		Loss of methylation at K625 (P = 2e-04)
MVP		0.014
MPC		0.14
ClinPred		0.021	T
GERP RS		-3.0
Varity_R		0.059
gMVP		0.085
Mutation Taster		=99/1	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: rs761041338; hg19: chr1-20009565;