chr8-144513073-C-A

Position:

• chr8-144513073-C-A

Variant summary

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

The NM_004260.4(RECQL4):​c.2529G>T​(p.Lys843Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K843K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.2529G>T	p.Lys843Asn	missense_variant	15/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.2529G>T	p.Lys843Asn	missense_variant	15/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4	c.1458G>T	p.Lys486Asn	missense_variant	14/20	1
	ENST00000580385.1	n.271+236C>A		intron_variant, non_coding_transcript_variant		3
RECQL4	ENST00000534626.6	c.702G>T	p.Lys234Asn	missense_variant	6/8	5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 66

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 19, 2022

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. ClinVar contains an entry for this variant (Variation ID: 657846). This variant has not been reported in the literature in individuals affected with RECQL4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 843 of the RECQL4 protein (p.Lys843Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.81
DEOGEN2	Benign	0.078	T;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.71	D;D
MutationAssessor	Benign	1.6	.;L
PrimateAI	Uncertain	0.59	T
Sift4G	Benign	0.18	T;D
Polyphen		0.78	.;P
Vest4		0.68
MVP		0.71
GERP RS		3.1
Varity_R		0.16
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1554897835; hg19: chr8-145738456;