12-7373530-T-G

Variant names:

• chr12-7373530-T-G
• rs117904047
• NM_174941.6:c.3520A>C

Variant summary

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

The NM_174941.6(CD163L1):​c.3520A>C​(p.Thr1174Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1174A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000057 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CD163L1 NM_174941.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.25
• Publications: 0 publications found

Genes affected

CD163L1 (HGNC:30375): (CD163 molecule like 1) This gene encodes a member of the scavenger receptor cysteine-rich (SRCR) superfamily. Members of this family are secreted or membrane-anchored proteins mainly found in cells associated with the immune system. The SRCR family is defined by a 100-110 amino acid SRCR domain, which may mediate protein-protein interaction and ligand binding. The encoded protein contains twelve SRCR domains, a transmembrane region and a cytoplasmic domain. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2014]

CD163L1 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.005140424).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174941.6. 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
	CD163L1	NM_174941.6	MANE Select	c.3520A>C	p.Thr1174Pro	missense	Exon 14 of 20	NP_777601.3	Q9NR16-1
	CD163L1	NM_001297650.2		c.3550A>C	p.Thr1184Pro	missense	Exon 14 of 20	NP_001284579.2	Q9NR16-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD163L1	ENST00000313599.8	TSL:1 MANE Select	c.3520A>C	p.Thr1174Pro	missense	Exon 14 of 20	ENSP00000315945.3	Q9NR16-1
	CD163L1	ENST00000416109.2	TSL:2	c.3550A>C	p.Thr1184Pro	missense	Exon 14 of 20	ENSP00000393474.2	Q9NR16-4
	CD163L1	ENST00000878199.1		c.3550A>C	p.Thr1184Pro	missense	Exon 14 of 19	ENSP00000548258.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000359 AC: 90 AN: 250710 AF XY: 0.000265

Gnomad AFR exome AF: 0.000868

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000837

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.00147

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000568 AC: 83 AN: 1461532 Hom.: 0 Cov.: 31 AF XY: 0.0000564 AC XY: 41 AN XY: 727060

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00143 AC: 76 AN: 53140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111976

Other (OTH) AF: 0.0000497 AC: 3 AN: 60360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000323 Hom.: 0

ExAC AF: 0.00250 AC: 303

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.10
DANN	Benign	0.75
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.075	N
PhyloP100		-3.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.020
Sift	Benign	0.19	T
Sift4G	Benign	0.28	T
Polyphen		0.010	B
Vest4		0.070
MutPred		0.61		Gain of catalytic residue at T1174 (P = 3e-04)
MVP		0.24
MPC		0.28
ClinPred		0.0021	T
GERP RS		-4.6
Varity_R		0.092
gMVP		0.39
Mutation Taster		=98/2	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: rs117904047; hg19: chr12-7526126;