rs573444137

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr19-49398101-G-A
• chr19-49398101-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_144688.5(KASH5):​c.587G>A​(p.Arg196His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,605,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. R196C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000018 (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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019143403).

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>A	p.Arg196His	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>A	p.Arg196His	missense	Exon 7 of 20	ENSP00000404220.2	Q8N6L0
	KASH5	ENST00000600570.1	TSL:2	c.476G>A	p.Arg159His	missense	Exon 5 of 18	ENSP00000470819.1	M0QZW6
	KASH5	ENST00000595828.5	TSL:5	c.545G>A	p.Arg182His	missense	Exon 8 of 8	ENSP00000471777.1	M0R1C7

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152104 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000324 AC: 8 AN: 247136 AF XY: 0.0000298

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000179 AC: 26 AN: 1453420 Hom.: 0 Cov.: 35 AF XY: 0.0000208 AC XY: 15 AN XY: 721224

African (AFR) AF: 0.0000900 AC: 3 AN: 33324

American (AMR) AF: 0.0000225 AC: 1 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: 0.000116 AC: 10 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: 0.00000995 AC: 11 AN: 1105384

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

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152222 Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 4 AN XY: 74438

African (AFR) AF: 0.0000482 AC: 2 AN: 41518

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000330 AC: 4

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	0.074
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.018
Sift	Benign	0.15	T
Sift4G	Uncertain	0.053	T
Polyphen		0.0030	B
Vest4		0.16
MutPred		0.13		Loss of helix (P = 0.0558)
MVP		0.16
MPC		0.18
ClinPred		0.046	T
GERP RS		1.8
Varity_R		0.049
gMVP		0.62
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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; COSMIC: COSV71357964; COSMIC: COSV71357964;