20-5772960-A-G

Variant names:

• chr20-5772960-A-G
• NM_152504.4:c.95A>G

Variant summary

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

The NM_152504.4(SHLD1):​c.95A>G​(p.Gln32Arg) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SHLD1 NM_152504.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.320
• Publications: 0 publications found

Genes affected

SHLD1 (HGNC:26318): (shieldin complex subunit 1) Involved in negative regulation of double-strand break repair via homologous recombination; positive regulation of double-strand break repair via nonhomologous end joining; and positive regulation of isotype switching. Located in site of double-strand break. [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=0.08740091).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHLD1	NM_152504.4	c.95A>G	p.Gln32Arg	missense_variant	Exon 2 of 3	ENST00000303142.11	NP_689717.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHLD1	ENST00000303142.11	c.95A>G	p.Gln32Arg	missense_variant	Exon 2 of 3	1	NM_152504.4	ENSP00000305875.6
SHLD1	ENST00000442185.1	c.236A>G	p.Gln79Arg	missense_variant	Exon 3 of 4	3		ENSP00000410534.1
SHLD1	ENST00000445603.1	c.95A>G	p.Gln32Arg	missense_variant	Exon 3 of 4	3		ENSP00000399331.1
SHLD1	ENST00000378979.8	c.95A>G	p.Gln32Arg	missense_variant	Exon 2 of 3	2		ENSP00000368263.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.95A>G (p.Q32R) alteration is located in exon 2 (coding exon 1) of the C20orf196 gene. This alteration results from a A to G substitution at nucleotide position 95, causing the glutamine (Q) at amino acid position 32 to be replaced by an arginine (R). 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	Benign	0.076
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.031	.;T;.;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.62	T;T;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.087	T;T;T;T
MetaSVM	Benign	-0.94	T
PhyloP100		0.32
PROVEAN	Uncertain	-3.0	D;N;N;N
REVEL	Benign	0.060
Sift	Pathogenic	0.0	D;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.015	.;B;.;.
Vest4		0.11
MutPred		0.11		Gain of phosphorylation at S35 (P = 0.0774);Gain of phosphorylation at S35 (P = 0.0774);Gain of phosphorylation at S35 (P = 0.0774);.;
MVP		0.19
MPC		0.19
ClinPred		0.50	D
GERP RS		1.1
Varity_R		0.060
gMVP		0.088
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

hg19: chr20-5753606;