chr5-156954493-C-A

Variant names:

• chr5-156954493-C-A
• rs1357076236
• NM_138379.3:c.322G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_138379.3(TIMD4):​c.322G>T​(p.Gly108Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TIMD4 NM_138379.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.477

Genes affected

TIMD4 (HGNC:25132): (T cell immunoglobulin and mucin domain containing 4) Predicted to enable phosphatidylserine binding activity. Predicted to act upstream of or within apoptotic cell clearance. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMD4	NM_138379.3	c.322G>T	p.Gly108Cys	missense_variant	Exon 2 of 9	ENST00000274532.7	NP_612388.2
TIMD4	NM_001146726.2	c.322G>T	p.Gly108Cys	missense_variant	Exon 2 of 8		NP_001140198.1
TIMD4	XM_017010021.2	c.322G>T	p.Gly108Cys	missense_variant	Exon 2 of 7		XP_016865510.1
TIMD4	XM_011534694.3	c.322G>T	p.Gly108Cys	missense_variant	Exon 2 of 6		XP_011532996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMD4	ENST00000274532.7	c.322G>T	p.Gly108Cys	missense_variant	Exon 2 of 9	1	NM_138379.3	ENSP00000274532.2
TIMD4	ENST00000407087.4	c.322G>T	p.Gly108Cys	missense_variant	Exon 2 of 8	2		ENSP00000385973.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74368

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.6	H;H
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-7.6	D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.52
MutPred		0.89		Loss of disorder (P = 0.0564);Loss of disorder (P = 0.0564);
MVP		0.40
MPC		0.35
ClinPred		0.93	D
GERP RS		-0.73
Varity_R		0.70
gMVP		0.83

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: rs1357076236; hg19: chr5-156381504;