17-44967925-C-T

Variant summary

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

The NM_006688.5(C1QL1):c.124G>A(p.Ala42Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000969 in 1,269,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000087 (0 hom.)
• Consequence: C1QL1 NM_006688.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.217

Genes affected

C1QL1 (HGNC:24182): (complement C1q like 1) Predicted to enable signaling receptor binding activity. Predicted to act upstream of or within maintenance of synapse structure; motor learning; and neuron remodeling. Predicted to be located in several cellular components, including climbing fiber; presynapse; and synaptic cleft. Predicted to be part of collagen trimer. [provided by Alliance of Genome Resources, Apr 2022]

NMT1 (HGNC:7857): (N-myristoyltransferase 1) Myristate, a rare 14-carbon saturated fatty acid, is cotranslationally attached by an amide linkage to the N-terminal glycine residue of cellular and viral proteins with diverse functions. N-myristoyltransferase (NMT; EC 2.3.1.97) catalyzes the transfer of myristate from CoA to proteins. N-myristoylation appears to be irreversible and is required for full expression of the biologic activities of several N-myristoylated proteins, including the alpha subunit of the signal-transducing guanine nucleotide-binding protein (G protein) GO (GNAO1; MIM 139311) (Duronio et al., 1992 [PubMed 1570339]).[supplied by OMIM, Nov 2008]

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=0.016444921).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1QL1	NM_006688.5	c.124G>A	p.Ala42Thr	missense_variant	1/2	ENST00000253407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1QL1	ENST00000253407.4	c.124G>A	p.Ala42Thr	missense_variant	1/2	1	NM_006688.5	P1
NMT1	ENST00000678938.1	c.-110+9863C>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.000173 AC: 26 AN: 150320 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000397

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: 0.0000890

Gnomad OTH AF: 0.000483

GnomAD3 exomes AF: 0.000189 AC: 10 AN: 52972 Hom.: 0 AF XY: 0.000229 AC XY: 7 AN XY: 30610

Gnomad AFR exome AF: 0.000298

Gnomad AMR exome AF: 0.000192

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000225

Gnomad OTH exome AF: 0.00109

GnomAD4 exome AF: 0.0000867 AC: 97 AN: 1118832 Hom.: 0 Cov.: 31 AF XY: 0.0000891 AC XY: 48 AN XY: 538452

Gnomad4 AFR exome AF: 0.000300

Gnomad4 AMR exome AF: 0.000159

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: 0.0000815

Gnomad4 OTH exome AF: 0.000159

GnomAD4 genome AF: 0.000173 AC: 26 AN: 150428 Hom.: 0 Cov.: 31 AF XY: 0.000191 AC XY: 14 AN XY: 73482

Gnomad4 AFR AF: 0.000315

Gnomad4 AMR AF: 0.000396

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000891

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000178

ExAC AF: 0.000102 AC: 11

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

Feb 13, 2023

The c.124G>A (p.A42T) alteration is located in exon 1 (coding exon 1) of the C1QL1 gene. This alteration results from a G to A substitution at nucleotide position 124, causing the alanine (A) at amino acid position 42 to be replaced by a threonine (T). 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	0.069
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.60	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.13	N
REVEL	Benign	0.23
Sift	Benign	0.91	T
Sift4G	Benign	0.88	T
Polyphen		0.0	B
Vest4		0.078
MutPred		0.25		Gain of phosphorylation at A42 (P = 0.0099);
MVP		0.25
ClinPred		0.0053	T
GERP RS		-3.5
Varity_R		0.036
gMVP		0.16

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: rs552223248; hg19: chr17-43045293;