5-169594163-G-C

Variant names:

• chr5-169594163-G-C
• rs529963287
• NM_017785.5:c.550G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017785.5(SPDL1):​c.550G>C​(p.Val184Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V184M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPDL1 NM_017785.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.177
• Publications: 0 publications found

Genes affected

SPDL1 (HGNC:26010): (spindle apparatus coiled-coil protein 1) This gene encodes a coiled-coil domain-containing protein that functions in mitotic spindle formation and chromosome segregation. The encoded protein plays a role in coordinating microtubule attachment by promoting recruitment of dynein proteins, and in mitotic checkpoint signaling. [provided by RefSeq, Jul 2016]

SPDL1 Gene-Disease associations (from GenCC):

• microcephaly

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04062414).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017785.5. 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
	SPDL1	NM_017785.5	MANE Select	c.550G>C	p.Val184Leu	missense	Exon 5 of 12	NP_060255.3
	SPDL1	NM_001329639.2		c.550G>C	p.Val184Leu	missense	Exon 5 of 11	NP_001316568.1
	SPDL1	NM_001329640.2		c.550G>C	p.Val184Leu	missense	Exon 5 of 11	NP_001316569.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPDL1	ENST00000265295.9	TSL:1 MANE Select	c.550G>C	p.Val184Leu	missense	Exon 5 of 12	ENSP00000265295.4	Q96EA4-1
	SPDL1	ENST00000507232.5	TSL:1	n.*330G>C		non_coding_transcript_exon	Exon 5 of 11	ENSP00000425357.1	D6RDK5
	SPDL1	ENST00000510751.5	TSL:1	n.707G>C		non_coding_transcript_exon	Exon 5 of 8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.38
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.65
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.18
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.022
Sift	Benign	0.60	T
Sift4G	Benign	0.65	T
Polyphen		0.0090	B
Vest4		0.26
MutPred		0.18		Gain of catalytic residue at V184 (P = 0.0098)
MVP		0.34
MPC		0.033
ClinPred		0.039	T
GERP RS		2.9
Varity_R		0.022
gMVP		0.037
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs529963287; hg19: chr5-169021167;