5-169588463-C-T

Variant names:

• chr5-169588463-C-T
• rs559833981
• NM_017785.5:c.47C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001329642.2(SPDL1):​c.-241C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000955 in 1,613,372 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000099 (1 hom.)
• Consequence: SPDL1 NM_001329642.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.163

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009505808).
• BP6: Variant 5-169588463-C-T is Benign according to our data. Variant chr5-169588463-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2403906.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPDL1	NM_017785.5	c.47C>T	p.Ala16Val	missense_variant	Exon 2 of 12	ENST00000265295.9	NP_060255.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPDL1	ENST00000265295.9	c.47C>T	p.Ala16Val	missense_variant	Exon 2 of 12	1	NM_017785.5	ENSP00000265295.4

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000116 AC: 29 AN: 250556 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135426

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000656

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000986 AC: 144 AN: 1461154 Hom.: 1 Cov.: 30 AF XY: 0.000128 AC XY: 93 AN XY: 726846

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000755

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74436

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jun 18, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.7
DANN	Benign	0.82
DEOGEN2	Benign	0.0059	T;T;T;.;T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.62	T;T;T;T;T;T;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.0095	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.17	N;.;.;.;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	N;N;N;.;N;N;N
REVEL	Benign	0.068
Sift	Benign	0.34	T;T;T;.;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T;T;T
Polyphen		0.0010	B;.;.;.;.;.;.
Vest4		0.039
MutPred		0.15		Loss of disorder (P = 0.055);Loss of disorder (P = 0.055);Loss of disorder (P = 0.055);Loss of disorder (P = 0.055);Loss of disorder (P = 0.055);Loss of disorder (P = 0.055);Loss of disorder (P = 0.055);
MVP		0.099
MPC		0.032
ClinPred		0.032	T
GERP RS		-5.3
Varity_R		0.023
gMVP		0.056

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: rs559833981; hg19: chr5-169015467;