6-145923763-C-A

Position:

• chr6-145923763-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001042683.3(SHPRH):​c.3425G>T​(p.Trp1142Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHPRH NM_001042683.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.80

Genes affected

SHPRH (HGNC:19336): (SNF2 histone linker PHD RING helicase) SHPRH is a ubiquitously expressed protein that contains motifs characteristics of several DNA repair proteins, transcription factors, and helicases. SHPRH is a functional homolog of S. cerevisiae RAD5 (Unk et al., 2006 [PubMed 17108083]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SHPRH

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHPRH	NM_001042683.3	c.3425G>T	p.Trp1142Leu	missense_variant	18/30	ENST00000275233.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHPRH	ENST00000275233.12	c.3425G>T	p.Trp1142Leu	missense_variant	18/30	1	NM_001042683.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2023

The c.3425G>T (p.W1142L) alteration is located in exon 18 (coding exon 17) of the SHPRH gene. This alteration results from a G to T substitution at nucleotide position 3425, causing the tryptophan (W) at amino acid position 1142 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.;.;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.0	M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-11	D;D;.;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0040	D;D;.;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.64
MutPred		0.62		Loss of helix (P = 0.0041);.;.;Loss of helix (P = 0.0041);
MVP		0.98
MPC		2.0
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.94
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-146244899;