1-201484762-T-A

Variant names:

• chr1-201484762-T-A
• rs951496754
• NM_004078.3:c.533A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004078.3(CSRP1):​c.533A>T​(p.Lys178Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,964 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: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CSRP1 NM_004078.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.95

Genes affected

CSRP1 (HGNC:2469): (cysteine and glycine rich protein 1) This gene encodes a member of the cysteine-rich protein (CSRP) family. This gene family includes a group of LIM domain proteins, which may be involved in regulatory processes important for development and cellular differentiation. The LIM/double zinc-finger motif found in this gene product occurs in proteins with critical functions in gene regulation, cell growth, and somatic differentiation. Alternatively spliced transcript variants have been described. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSRP1	NM_004078.3	c.533A>T	p.Lys178Met	missense_variant	Exon 6 of 6	ENST00000340006.7	NP_004069.1
CSRP1	NM_001193571.2	c.533A>T	p.Lys178Met	missense_variant	Exon 6 of 6		NP_001180500.1
CSRP1	NM_001193572.2	c.533A>T	p.Lys178Met	missense_variant	Exon 6 of 6		NP_001180501.1
CSRP1	NM_001193570.2	c.515A>T	p.Lys172Met	missense_variant	Exon 6 of 6		NP_001180499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSRP1	ENST00000340006.7	c.533A>T	p.Lys178Met	missense_variant	Exon 6 of 6	1	NM_004078.3	ENSP00000345079.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246488 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132992

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459964 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 725990

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000672

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.533A>T (p.K178M) alteration is located in exon 6 (coding exon 5) of the CSRP1 gene. This alteration results from a A to T substitution at nucleotide position 533, causing the lysine (K) at amino acid position 178 to be replaced by a methionine (M). 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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;T;T;T;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;.;.;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.0	D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.
Polyphen		1.0	D;D;D;D;.;.
Vest4		0.62
MutPred		0.49		Loss of catalytic residue at K178 (P = 0.007);Loss of catalytic residue at K178 (P = 0.007);Loss of catalytic residue at K178 (P = 0.007);Loss of catalytic residue at K178 (P = 0.007);.;.;
MVP		0.99
MPC		0.96
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.71
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs951496754; hg19: chr1-201453890;