1-201488887-A-G

Variant names:

• chr1-201488887-A-G
• rs1191183763
• NM_004078.3:c.379T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004078.3(CSRP1):​c.379T>C​(p.Tyr127His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. Y127C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSRP1 NM_004078.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.28

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSRP1	NM_004078.3	c.379T>C	p.Tyr127His	missense_variant	Exon 4 of 6	ENST00000340006.7	NP_004069.1
CSRP1	NM_001193571.2	c.379T>C	p.Tyr127His	missense_variant	Exon 4 of 6		NP_001180500.1
CSRP1	NM_001193572.2	c.379T>C	p.Tyr127His	missense_variant	Exon 4 of 6		NP_001180501.1
CSRP1	NM_001193570.2	c.379T>C	p.Tyr127His	missense_variant	Exon 4 of 6		NP_001180499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSRP1	ENST00000340006.7	c.379T>C	p.Tyr127His	missense_variant	Exon 4 of 6	1	NM_004078.3	ENSP00000345079.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.379T>C (p.Y127H) alteration is located in exon 4 (coding exon 3) of the CSRP1 gene. This alteration results from a T to C substitution at nucleotide position 379, causing the tyrosine (Y) at amino acid position 127 to be replaced by a histidine (H). 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	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;D;T;D;D;D;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	.;D;D;.;.;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Pathogenic	3.2	M;M;.;M;M;.;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0080	D;D;D;D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D;D;D;.
Polyphen		0.063	B;B;.;B;B;.;.
Vest4		0.81
MutPred		0.63		Gain of disorder (P = 0.012);Gain of disorder (P = 0.012);Gain of disorder (P = 0.012);Gain of disorder (P = 0.012);Gain of disorder (P = 0.012);.;.;
MVP		0.95
MPC		0.49
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.64
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1191183763; hg19: chr1-201458015;