chr5-98856663-G-A

Position:

• chr5-98856663-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001270.4(CHD1):​c.4850C>T​(p.Ser1617Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD1 NM_001270.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.62

Genes affected

CHD1 (HGNC:1915): (chromodomain helicase DNA binding protein 1) The CHD family of proteins is characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. CHD genes alter gene expression possibly by modification of chromatin structure thus altering access of the transcriptional apparatus to its chromosomal DNA template. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CHD1. . Trascript score misZ 3.2778 (greater than threshold 3.09). GenCC has associacion of gene with Pilarowski-Bjornsson syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07962564).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD1	NM_001270.4	c.4850C>T	p.Ser1617Leu	missense_variant	36/36	ENST00000614616.5	NP_001261.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD1	ENST00000614616.5	c.4850C>T	p.Ser1617Leu	missense_variant	36/36	5	NM_001270.4	ENSP00000483667	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 23, 2024

Variant summary: CHD1 c.4850C>T (p.Ser1617Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251040 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4850C>T in individuals affected with Pilarowski-Bjornsson Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2504896). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 08, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.072	T;T
Eigen	Benign	0.019
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.080	T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.2	.;N
REVEL	Uncertain	0.30
Sift	Benign	0.62	.;T
Sift4G	Benign	0.34	T;T
Polyphen		0.0	B;B
Vest4		0.078
MutPred		0.18		Loss of phosphorylation at S1617 (P = 0.0054);Loss of phosphorylation at S1617 (P = 0.0054);
MVP		0.52
MPC		0.034
ClinPred		0.79	D
GERP RS		5.5
Varity_R		0.11
gMVP		0.30

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-98192367;