1-222994871-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001377229.1(DISP1):​c.890-14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,572,070 control chromosomes in the GnomAD database, including 84,439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9733 hom., cov: 32)
  • Exomes 𝑓: 0.32 (74706 hom.)
• Consequence: DISP1 NM_001377229.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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: AR, AD, SD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Illumina

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 1-222994871-T-C is Benign according to our data. Variant chr1-222994871-T-C is described in ClinVar as Benign. ClinVar VariationId is 262132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DISP1	NM_001377229.1	c.890-14T>C		intron_variant	Intron 7 of 8	ENST00000675850.1	NP_001364158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DISP1	ENST00000675850.1	c.890-14T>C		intron_variant	Intron 7 of 8		NM_001377229.1	ENSP00000502357.1

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53280 AN: 151808 Hom.: 9713 Cov.: 32

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.448

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.325

GnomAD2 exomes AF: 0.344 AC: 85707 AN: 249154 AF XY: 0.347

Gnomad AFR exome AF: 0.433

Gnomad AMR exome AF: 0.375

Gnomad ASJ exome AF: 0.285

Gnomad EAS exome AF: 0.300

Gnomad FIN exome AF: 0.363

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.328

GnomAD4 exome AF: 0.319 AC: 452437 AN: 1420144 Hom.: 74706 Cov.: 25 AF XY: 0.322 AC XY: 228138 AN XY: 709418

African (AFR) AF: 0.428 AC: 13906 AN: 32500

American (AMR) AF: 0.369 AC: 16418 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 7473 AN: 25866

East Asian (EAS) AF: 0.282 AC: 11103 AN: 39418

South Asian (SAS) AF: 0.451 AC: 38407 AN: 85118

European-Finnish (FIN) AF: 0.356 AC: 18606 AN: 52330

Middle Eastern (MID) AF: 0.272 AC: 1417 AN: 5216

European-Non Finnish (NFE) AF: 0.303 AC: 325905 AN: 1076252

Other (OTH) AF: 0.326 AC: 19202 AN: 58948

GnomAD4 genome AF: 0.351 AC: 53346 AN: 151926 Hom.: 9733 Cov.: 32 AF XY: 0.355 AC XY: 26383 AN XY: 74228

African (AFR) AF: 0.436 AC: 18059 AN: 41426

American (AMR) AF: 0.338 AC: 5148 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 986 AN: 3466

East Asian (EAS) AF: 0.296 AC: 1532 AN: 5180

South Asian (SAS) AF: 0.446 AC: 2139 AN: 4798

European-Finnish (FIN) AF: 0.376 AC: 3961 AN: 10522

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.299 AC: 20336 AN: 67976

Other (OTH) AF: 0.328 AC: 691 AN: 2108

Alfa AF: 0.253 Hom.: 1265

Bravo AF: 0.352

Asia WGS AF: 0.408 AC: 1419 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.9
DANN	Benign	0.84
PhyloP100		0.077
Mutation Taster		=100/0	polymorphism (auto)

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: rs2609359; hg19: chr1-223168213; COSMIC: COSV52656379;