NM_006367.4:c.433G>T

Variant names:

• chr1-40064365-G-T
• rs1646985456
• NM_006367.4:c.433G>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_006367.4(CAP1):​c.433G>T​(p.Ala145Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CAP1 NM_006367.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.19

Genes affected

CAP1 (HGNC:20040): (cyclase associated actin cytoskeleton regulatory protein 1) The protein encoded by this gene is related to the S. cerevisiae CAP protein, which is involved in the cyclic AMP pathway. The human protein is able to interact with other molecules of the same protein, as well as with CAP2 and actin. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAP1	NM_006367.4	c.433G>T	p.Ala145Ser	missense_variant	Exon 5 of 13	ENST00000372805.8	NP_006358.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAP1	ENST00000372805.8	c.433G>T	p.Ala145Ser	missense_variant	Exon 5 of 13	1	NM_006367.4	ENSP00000361891.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 02, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.433G>T (p.A145S) alteration is located in exon 5 (coding exon 4) of the CAP1 gene. This alteration results from a G to T substitution at nucleotide position 433, causing the alanine (A) at amino acid position 145 to be replaced by a serine (S). 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	0.19
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	T;.;T;T;T;T;T;.;.;T;.;T;T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;D;D;D;D;.;.;D;D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.;.;.;.;.;M;.;.;M;.;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.17	T;T;T;T;T;T;T;T;T;T;D;D;T;D
Sift4G	Benign	0.18	T;T;D;D;D;D;T;T;T;T;D;D;D;D
Polyphen		0.99	D;.;.;.;.;.;D;.;.;D;.;.;.;.
Vest4		0.66
MutPred		0.78		Gain of disorder (P = 0.1126);.;Gain of disorder (P = 0.1126);Gain of disorder (P = 0.1126);Gain of disorder (P = 0.1126);Gain of disorder (P = 0.1126);Gain of disorder (P = 0.1126);.;.;Gain of disorder (P = 0.1126);.;Gain of disorder (P = 0.1126);Gain of disorder (P = 0.1126);Gain of disorder (P = 0.1126);
MVP		0.46
MPC		0.82
ClinPred		0.93	D
GERP RS		5.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.59
gMVP		0.33

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: rs1646985456; hg19: chr1-40530037;