8-144516485-G-T

Position:

• chr8-144516485-G-T

Variant summary

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

The NM_004260.4(RECQL4):​c.634C>A​(p.Leu212Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,550 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L212R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.171

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 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=0.1376405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.634C>A	p.Leu212Ile	missense_variant	5/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.634C>A	p.Leu212Ile	missense_variant	5/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4	c.-438C>A		5_prime_UTR_variant	4/20	1
RECQL4	ENST00000524998.1	c.228-72C>A		intron_variant		3
RECQL4	ENST00000534538.1	c.*438C>A		3_prime_UTR_variant, NMD_transcript_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456550 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 724638

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Baller-Gerold syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 16, 2020

This sequence change replaces leucine with isoleucine at codon 212 of the RECQL4 protein (p.Leu212Ile). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RECQL4-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	8.6
DANN	Benign	0.72
DEOGEN2	Benign	0.054	T
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.14	T
PrimateAI	Benign	0.29	T
Sift4G	Benign	0.28	T
Polyphen		0.60	P
Vest4		0.26
MVP		0.62
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.053

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: rs377012693; hg19: chr8-145741869;