chrX-100914451-T-C

Position:

• chrX-100914451-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_212559.3(XKRX):​c.1237A>G​(p.Thr413Ala) 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: XKRX NM_212559.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.398

Genes affected

XKRX (HGNC:29845): (XK related X-linked) This gene encodes a protein that is related to a component of the XK/Kell complex of the Kell blood group system. The encoded protein includes several transmembrane domains, is known to be exposed to the cell surface, and may function as a membrane transporter. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0887962).
• BP6: Variant X-100914451-T-C is Benign according to our data. Variant chrX-100914451-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2207843.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XKRX	NM_212559.3	c.1237A>G	p.Thr413Ala	missense_variant	3/3	ENST00000372956.3	NP_997724.2
XKRX	XM_011530955.2	c.889A>G	p.Thr297Ala	missense_variant	4/4		XP_011529257.1
XKRX	XM_017029517.2	c.625A>G	p.Thr209Ala	missense_variant	2/2		XP_016885006.1
XKRX	XM_011530954.4	c.1106+170A>G		intron_variant			XP_011529256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XKRX	ENST00000372956.3	c.1237A>G	p.Thr413Ala	missense_variant	3/3	1	NM_212559.3	ENSP00000362047.2
XKRX	ENST00000468904.1	c.*548A>G		3_prime_UTR_variant	2/2	2		ENSP00000419884.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

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	0.081
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	14
DANN	Benign	0.85
DEOGEN2	Benign	0.011	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.054
Sift	Benign	0.11	T
Sift4G	Benign	0.43	T
Polyphen		0.042	B
Vest4		0.020
MVP		0.11
MPC		0.10
ClinPred		0.079	T
GERP RS		3.4
Varity_R		0.051
gMVP		0.21

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: rs1473518092; hg19: chrX-100169440;