Genetic Variant NM_144688.5:c.359C>A (chr19-49395792-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_144688.5(KASH5):c.359C>A(p.Thr120Asn) 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. 13/22 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. T120I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KASH5
NM_144688.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.17

Publications

0 publications found

Variant links:

Genes affected

KASH5 (HGNC:26520): (KASH domain containing 5) Predicted to enable dynein complex binding activity. Predicted to be involved in several processes, including cytoskeleton organization; homologous chromosome segregation; and spindle localization. Predicted to act upstream of or within double-strand break repair via homologous recombination; oogenesis; and spermatogenesis. Predicted to be integral component of membrane. Predicted to be part of meiotic nuclear membrane microtubule tethering complex. Predicted to be active in chromosome; meiotic spindle pole; and nuclear outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

KASH5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2042686).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144688.5. 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
	KASH5	NM_144688.5	MANE Select	c.359C>A	p.Thr120Asn	missense	Exon 5 of 20	NP_653289.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KASH5	ENST00000447857.8	TSL:1 MANE Select	c.359C>A	p.Thr120Asn	missense	Exon 5 of 20	ENSP00000404220.2	Q8N6L0
KASH5	ENST00000600570.1	TSL:2	c.248C>A	p.Thr83Asn	missense	Exon 3 of 18	ENSP00000470819.1	M0QZW6
KASH5	ENST00000594043.5	TSL:3	c.359C>A	p.Thr120Asn	missense	Exon 5 of 7	ENSP00000469435.1	M0QXW9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1411954

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

697734

African (AFR)

AF:

0.00

AC:

AN:

32282

American (AMR)

AF:

0.00

AC:

AN:

37772

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25308

East Asian (EAS)

AF:

0.00

AC:

AN:

36924

South Asian (SAS)

AF:

0.00

AC:

AN:

79806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49946

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5054

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086418

Other (OTH)

AF:

0.00

AC:

AN:

58444

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.056

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.72

M_CAP

Benign

0.0063

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.1

PhyloP100

2.2

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.3

REVEL

Benign

0.090

Sift

Benign

0.055

Sift4G

Uncertain

0.013

Polyphen

0.97

Vest4

0.30

MutPred

0.14

Loss of phosphorylation at T120 (P = 0.0884)

MVP

0.59

MPC

0.38

ClinPred

0.88

GERP RS

4.4

Varity_R

0.14

gMVP

0.80

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over