rs373187237

Variant names:

• chr8-144513099-C-A
• rs373187237
• NM_004260.4:c.2503G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-144513099-C-A
• chr8-144513099-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004260.4(RECQL4):​c.2503G>T​(p.Asp835Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,420,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D835N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.321
• Publications: 0 publications found

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]

RECQL4 Gene-Disease associations (from GenCC):

• Baller-Gerold syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet
• Rothmund-Thomson syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Rothmund-Thomson syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• osteosarcoma

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• rapadilino syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ENSG00000265393 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26608476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.2503G>T	p.Asp835Tyr	missense_variant	Exon 15 of 21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.2503G>T	p.Asp835Tyr	missense_variant	Exon 15 of 21	1	NM_004260.4	ENSP00000482313.2
RECQL4	ENST00000621189.4	c.1432G>T	p.Asp478Tyr	missense_variant	Exon 14 of 20	1		ENSP00000483145.1
RECQL4	ENST00000534626.6	c.673G>T	p.Asp225Tyr	missense_variant	Exon 6 of 8	5		ENSP00000477457.1
ENSG00000265393	ENST00000580385.1	n.271+262C>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1420650 Hom.: 0 Cov.: 66 AF XY: 0.00 AC XY: 0 AN XY: 701418

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32706

American (AMR) AF: 0.00 AC: 0 AN: 41498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23902

East Asian (EAS) AF: 0.00 AC: 0 AN: 38724

South Asian (SAS) AF: 0.00 AC: 0 AN: 80746

European-Finnish (FIN) AF: 0.0000201 AC: 1 AN: 49864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089046

Other (OTH) AF: 0.00 AC: 0 AN: 58540

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	7.0
DANN	Benign	0.55
DEOGEN2	Benign	0.16	T;T
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.27	T;T
MutationAssessor	Benign	1.9	.;L
PhyloP100		-0.32
PrimateAI	Benign	0.30	T
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.99	.;D
Vest4		0.35
MVP		0.69
GERP RS		-9.8
PromoterAI		0.029	Neutral
Varity_R		0.048
gMVP		0.72
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs373187237; hg19: chr8-145738482;