4-158960298-T-C

Position:

• chr4-158960298-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152543.3(C4orf45):​c.344A>G​(p.Tyr115Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,403,434 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: C4orf45 NM_152543.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13

Genes affected

C4orf45 (HGNC:):

SPMIP2 (HGNC:26342): (sperm microtubule inner protein 2)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C4orf45	NM_152543.3	c.344A>G	p.Tyr115Cys	missense_variant	3/5	ENST00000434826.3	NP_689756.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPMIP2	ENST00000434826.3	c.344A>G	p.Tyr115Cys	missense_variant	3/5	2	NM_152543.3	ENSP00000412215	P1
SPMIP2	ENST00000505647.1	n.53+12781A>G		intron_variant, non_coding_transcript_variant		3
SPMIP2	ENST00000508011.1	n.392+12781A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1403434 Hom.: 0 Cov.: 25 AF XY: 0.00000143 AC XY: 1 AN XY: 700506

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: 9.39e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Aug 02, 2021

The c.344A>G (p.Y115C) alteration is located in exon 3 (coding exon 3) of the C4orf45 gene. This alteration results from a A to G substitution at nucleotide position 344, causing the tyrosine (Y) at amino acid position 115 to be replaced by a cysteine (C). 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	0.32
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.77	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.38		Loss of glycosylation at P118 (P = 0.0605);
MVP		0.23
MPC		0.019
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.45
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1732199483; hg19: chr4-159881450;