1-222994871-T-G

Variant names:

• chr1-222994871-T-G
• rs2609359
• NM_001377229.1:c.890-14T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001377229.1(DISP1):​c.890-14T>G variant causes a intron 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DISP1 NM_001377229.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0770
• Publications: 6 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: SD, AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Illumina, ClinGen, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).

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.890-14T>G		intron	N/A	NP_001364158.1	Q96F81
	DISP1	NM_001369594.1		c.890-14T>G		intron	N/A	NP_001356523.1	Q96F81
	DISP1	NM_001377228.1		c.890-14T>G		intron	N/A	NP_001364157.1	Q96F81

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISP1	ENST00000675850.1	MANE Select	c.890-14T>G		intron	N/A	ENSP00000502357.1	Q96F81
	DISP1	ENST00000284476.7	TSL:1	c.890-14T>G		intron	N/A	ENSP00000284476.6	Q96F81
	DISP1	ENST00000900747.1		c.890-14T>G		intron	N/A	ENSP00000570806.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.04e-7 AC: 1 AN: 1421380 Hom.: 0 Cov.: 25 AF XY: 0.00000141 AC XY: 1 AN XY: 709942

⚠️ 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: 32532

American (AMR) AF: 0.00 AC: 0 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25870

East Asian (EAS) AF: 0.00 AC: 0 AN: 39428

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5220

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077304

Other (OTH) AF: 0.00 AC: 0 AN: 58992

⚠️ 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.: 32

Alfa AF: 0.00 Hom.: 1265

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.6
DANN	Benign	0.83
PhyloP100		0.077

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2609359; hg19: chr1-223168213;