9-36191208-C-T

Variant names:

• chr9-36191208-C-T
• rs1224331668
• NM_001833.4:c.152C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001833.4(CLTA):​c.152C>T​(p.Ala51Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000032 in 1,562,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. A51T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CLTA NM_001833.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.42
• Publications: 0 publications found

Genes affected

CLTA (HGNC:2090): (clathrin light chain A) Clathrin is a large, soluble protein composed of heavy and light chains. It functions as the main structural component of the lattice-type cytoplasmic face of coated pits and vesicles which entrap specific macromolecules during receptor-mediated endocytosis. This gene encodes one of two clathrin light chain proteins which are believed to function as regulatory elements. Alternative splicing results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 8 and 12. [provided by RefSeq, May 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12835816).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001833.4. 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
	CLTA	NM_001833.4	MANE Select	c.152C>T	p.Ala51Val	missense	Exon 1 of 5	NP_001824.1	P09496-2
	CLTA	NM_007096.4		c.152C>T	p.Ala51Val	missense	Exon 1 of 7	NP_009027.1	P09496-1
	CLTA	NM_001076677.3		c.152C>T	p.Ala51Val	missense	Exon 1 of 6	NP_001070145.1	P09496-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLTA	ENST00000345519.10	TSL:1 MANE Select	c.152C>T	p.Ala51Val	missense	Exon 1 of 5	ENSP00000242284.6	P09496-2
	CLTA	ENST00000242285.11	TSL:1	c.152C>T	p.Ala51Val	missense	Exon 1 of 7	ENSP00000242285.6	P09496-1
	CLTA	ENST00000396603.6	TSL:1	c.152C>T	p.Ala51Val	missense	Exon 1 of 6	ENSP00000379848.2	P09496-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000284 AC: 4 AN: 1410682 Hom.: 0 Cov.: 31 AF XY: 0.00000287 AC XY: 2 AN XY: 698036

African (AFR) AF: 0.00 AC: 0 AN: 31886

American (AMR) AF: 0.00 AC: 0 AN: 37776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25312

East Asian (EAS) AF: 0.00 AC: 0 AN: 36542

South Asian (SAS) AF: 0.00 AC: 0 AN: 81202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4594

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1090202

Other (OTH) AF: 0.0000171 AC: 1 AN: 58534

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

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

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

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	0.29
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.090	N
PhyloP100		4.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.048
Sift	Benign	0.17	T
Sift4G	Benign	0.23	T
Polyphen		0.032	B
Vest4		0.16
MutPred		0.47		Gain of sheet (P = 0.0266)
MVP		0.26
MPC		0.55
ClinPred		0.69	D
GERP RS		4.5
PromoterAI		-0.30	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.57
gMVP		0.41
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1224331668; hg19: chr9-36191205;