8-144511991-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_004260.4(RECQL4):c.3313G>A(p.Gly1105Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000595 in 1,610,456 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1105D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 35)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.389

Genes affected

RECQL4 (HGNC:9949): (RecQ like helicase 4) The protein encoded by this gene is a DNA helicase that belongs to the RecQ helicase family. DNA helicases unwind double-stranded DNA into single-stranded DNAs and may modulate chromosome segregation. This gene is predominantly expressed in thymus and testis. Mutations in this gene are associated with Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027576387).
• BP6: Variant 8-144511991-C-T is Benign according to our data. Variant chr8-144511991-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 135150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00271 (413/152358) while in subpopulation AFR AF= 0.00933 (388/41574). AF 95% confidence interval is 0.00857. There are 1 homozygotes in gnomad4. There are 205 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.3313G>A	p.Gly1105Ser	missense_variant	19/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.3313G>A	p.Gly1105Ser	missense_variant	19/21	1	NM_004260.4	P1

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 412 AN: 152240 Hom.: 1 Cov.: 35

Gnomad AFR AF: 0.00934

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000650 AC: 158 AN: 242956 Hom.: 0 AF XY: 0.000527 AC XY: 70 AN XY: 132752

Gnomad AFR exome AF: 0.00953

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000969

Gnomad NFE exome AF: 0.0000911

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000374 AC: 545 AN: 1458098 Hom.: 1 Cov.: 58 AF XY: 0.000324 AC XY: 235 AN XY: 725266

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.000180

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.0000781

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.000531

GnomAD4 genome AF: 0.00271 AC: 413 AN: 152358 Hom.: 1 Cov.: 35 AF XY: 0.00275 AC XY: 205 AN XY: 74512

Gnomad4 AFR AF: 0.00933

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000818 Hom.: 0

Bravo AF: 0.00290

ESP6500AA AF: 0.0107 AC: 45

ESP6500EA AF: 0.000237 AC: 2

ExAC AF: 0.000950 AC: 114

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 19, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 04, 2021

This variant is associated with the following publications: (PMID: 18504617) -

Baller-Gerold syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Oct 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.10
Dann	Benign	0.82
DEOGEN2	Benign	0.0033	T;T;T
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.48	T;T;T
MetaRNN	Benign	0.0028	T;T;T
PrimateAI	Benign	0.32	T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	.;B;.
Vest4		0.67
MVP		0.71
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.042
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: rs34915097; hg19: chr8-145737374; COSMIC: COSV100020311; COSMIC: COSV100020311;