rs146696975

Variant names:

• chr5-156951574-G-A
• rs146696975
• NM_138379.3:c.617C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_138379.3(TIMD4):​c.617C>T​(p.Pro206Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000849 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P206T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: TIMD4 NM_138379.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.737
• Publications: 1 publications found

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.06411776).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138379.3. 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
	TIMD4	NM_138379.3	MANE Select	c.617C>T	p.Pro206Leu	missense	Exon 3 of 9	NP_612388.2	Q96H15-1
	TIMD4	NM_001146726.2		c.617C>T	p.Pro206Leu	missense	Exon 3 of 8	NP_001140198.1	Q96H15-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMD4	ENST00000274532.7	TSL:1 MANE Select	c.617C>T	p.Pro206Leu	missense	Exon 3 of 9	ENSP00000274532.2	Q96H15-1
	TIMD4	ENST00000407087.4	TSL:2	c.617C>T	p.Pro206Leu	missense	Exon 3 of 8	ENSP00000385973.3	Q96H15-2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152106 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000107 AC: 27 AN: 251436 AF XY: 0.000155

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000862 AC: 126 AN: 1461828 Hom.: 0 Cov.: 31 AF XY: 0.000106 AC XY: 77 AN XY: 727226

African (AFR) AF: 0.0000598 AC: 2 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000899 AC: 100 AN: 1112002

Other (OTH) AF: 0.0000994 AC: 6 AN: 60388

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152106 Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 7 AN XY: 74294

African (AFR) AF: 0.00 AC: 0 AN: 41376

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000642

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.086
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.74
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.013
Sift	Benign	0.51	T
Sift4G	Benign	0.16	T
Polyphen		0.078	B
Vest4		0.14
MVP		0.31
MPC		0.055
ClinPred		0.013	T
GERP RS		2.1
Varity_R		0.050
gMVP		0.45
Mutation Taster		=100/0	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: rs146696975; hg19: chr5-156378585;