NM_144688.5:c.587G>T

Variant names:

• chr19-49398101-G-T
• rs573444137
• NM_144688.5:c.587G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144688.5(KASH5):​c.587G>T​(p.Arg196Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. R196H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KASH5 NM_144688.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35
• Publications: 0 publications found

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]

ACMG classification

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=0.12811592).

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.587G>T	p.Arg196Leu	missense	Exon 7 of 20	NP_653289.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KASH5	ENST00000447857.8	TSL:1 MANE Select	c.587G>T	p.Arg196Leu	missense	Exon 7 of 20	ENSP00000404220.2	Q8N6L0
	KASH5	ENST00000600570.1	TSL:2	c.476G>T	p.Arg159Leu	missense	Exon 5 of 18	ENSP00000470819.1	M0QZW6
	KASH5	ENST00000595828.5	TSL:5	c.545G>T	p.Arg182Leu	missense	Exon 8 of 8	ENSP00000471777.1	M0R1C7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453422 Hom.: 0 Cov.: 35 AF XY: 0.00000139 AC XY: 1 AN XY: 721224

African (AFR) AF: 0.00 AC: 0 AN: 33324

American (AMR) AF: 0.00 AC: 0 AN: 44460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25998

East Asian (EAS) AF: 0.00 AC: 0 AN: 39400

South Asian (SAS) AF: 0.00 AC: 0 AN: 85882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105386

Other (OTH) AF: 0.0000167 AC: 1 AN: 59950

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.4
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.095
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.16	B
Vest4		0.48
MutPred		0.21		Loss of MoRF binding (P = 0.0628)
MVP		0.37
MPC		0.31
ClinPred		0.72	D
GERP RS		1.8
Varity_R		0.20
gMVP		0.80
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs573444137; hg19: chr19-49901358;