12-31981273-C-G

Variant names:

• chr12-31981273-C-G
• rs2388981
• NM_018169.4:c.318C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018169.4(RESF1):​c.318C>G​(p.His106Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RESF1 NM_018169.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.71

Genes affected

RESF1 (HGNC:25559): (retroelement silencing factor 1) Predicted to enable histone binding activity and histone methyltransferase binding activity. Predicted to be involved in negative regulation of single stranded viral RNA replication via double stranded DNA intermediate and positive regulation of DNA methylation-dependent heterochromatin assembly. Predicted to act upstream of or within response to bacterium. Predicted to be located in nucleus. Predicted to colocalize with gamma-tubulin complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12308833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RESF1	NM_018169.4	c.318C>G	p.His106Gln	missense_variant	Exon 4 of 6	ENST00000312561.9	NP_060639.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RESF1	ENST00000312561.9	c.318C>G	p.His106Gln	missense_variant	Exon 4 of 6	1	NM_018169.4	ENSP00000310338.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461800 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.318C>G (p.H106Q) alteration is located in exon 4 (coding exon 1) of the KIAA1551 gene. This alteration results from a C to G substitution at nucleotide position 318, causing the histidine (H) at amino acid position 106 to be replaced by a glutamine (Q). 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	0.11
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.0060
DANN	Benign	0.49
DEOGEN2	Benign	0.054	T;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.032
Sift	Benign	0.20	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.0020	B;.
Vest4		0.060
MutPred		0.66		Loss of catalytic residue at L108 (P = 0.082);Loss of catalytic residue at L108 (P = 0.082);
MVP		0.040
MPC		0.010
ClinPred		0.072	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.069
gMVP		0.26

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: rs2388981; hg19: chr12-32134207;