1-222943130-G-C

Variant names:

• chr1-222943130-G-C
• rs2609383
• NM_001377229.1:c.307G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001377229.1(DISP1):​c.307G>C​(p.Glu103Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 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. E103D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DISP1 NM_001377229.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87
• Publications: 24 publications found

Genes affected

DISP1 (HGNC:19711): (dispatched RND transporter family member 1) The pattern of cellular proliferation and differentiation that leads to normal development of embryonic structures often depends upon the localized production of secreted protein signals. Cells surrounding the source of a particular signal respond in a graded manner according to the effective concentration of the signal, and this response produces the pattern of cell types constituting the mature structure. A novel segment-polarity gene known as dispatched has been identified in Drosophila and its protein product is required for normal Hedgehog (Hh) signaling. This gene is one of two human homologs of Drosophila dispatched and, based on sequence identity to its mouse counterpart, the encoded protein may play an essential role in Hh patterning activities in the early embryo. [provided by RefSeq, Jul 2008]

DISP1 Gene-Disease associations (from GenCC):

• holoprosencephaly

  Inheritance: AD, AR, SD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06926122).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377229.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISP1	NM_001377229.1	MANE Select	c.307G>C	p.Glu103Gln	missense	Exon 3 of 9	NP_001364158.1
	DISP1	NM_001369594.1		c.307G>C	p.Glu103Gln	missense	Exon 2 of 8	NP_001356523.1
	DISP1	NM_001377228.1		c.307G>C	p.Glu103Gln	missense	Exon 2 of 8	NP_001364157.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISP1	ENST00000675850.1	MANE Select	c.307G>C	p.Glu103Gln	missense	Exon 3 of 9	ENSP00000502357.1
	DISP1	ENST00000284476.7	TSL:1	c.307G>C	p.Glu103Gln	missense	Exon 2 of 8	ENSP00000284476.6
	DISP1	ENST00000482856.1	TSL:1	n.454G>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.22
Eigen_PC	Benign	0.0038
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.069	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.74	N
PhyloP100		1.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.18
Sift	Benign	0.48	T
Sift4G	Benign	0.43	T
Polyphen		0.0010	B
Vest4		0.049
MutPred		0.10		Gain of glycosylation at P106 (P = 0.1689)
MVP		0.73
MPC		0.18
ClinPred		0.15	T
GERP RS		4.7
Varity_R		0.13
gMVP		0.21
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs2609383; hg19: chr1-223116472;