rs9441941

Variant names:

• chr1-223005219-A-C
• rs9441941
• NM_001377229.1:c.3822A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-223005219-A-C
• chr1-223005219-A-G
• chr1-223005219-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001377229.1(DISP1):​c.3822A>C​(p.Pro1274Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,613,862 control chromosomes in the GnomAD database, including 256,752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21985 hom., cov: 33)
  • Exomes 𝑓: 0.57 (234767 hom.)
• Consequence: DISP1 NM_001377229.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.900
• Publications: 17 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-223005219-A-C is Benign according to our data. Variant chr1-223005219-A-C is described in ClinVar as Benign. ClinVar VariationId is 262131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.9 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

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.3822A>C	p.Pro1274Pro	synonymous	Exon 9 of 9	NP_001364158.1	Q96F81
	DISP1	NM_001369594.1		c.3822A>C	p.Pro1274Pro	synonymous	Exon 8 of 8	NP_001356523.1	Q96F81
	DISP1	NM_001377228.1		c.3822A>C	p.Pro1274Pro	synonymous	Exon 8 of 8	NP_001364157.1	Q96F81

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISP1	ENST00000675850.1	MANE Select	c.3822A>C	p.Pro1274Pro	synonymous	Exon 9 of 9	ENSP00000502357.1	Q96F81
	DISP1	ENST00000284476.7	TSL:1	c.3822A>C	p.Pro1274Pro	synonymous	Exon 8 of 8	ENSP00000284476.6	Q96F81
	DISP1	ENST00000900747.1		c.3849A>C	p.Pro1283Pro	synonymous	Exon 8 of 8	ENSP00000570806.1

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81238 AN: 151930 Hom.: 21985 Cov.: 33

Gnomad AFR AF: 0.451

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.549

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.494

Gnomad SAS AF: 0.471

Gnomad FIN AF: 0.584

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.540

GnomAD2 exomes AF: 0.547 AC: 137015 AN: 250608 AF XY: 0.545

Gnomad AFR exome AF: 0.447

Gnomad AMR exome AF: 0.538

Gnomad ASJ exome AF: 0.558

Gnomad EAS exome AF: 0.513

Gnomad FIN exome AF: 0.594

Gnomad NFE exome AF: 0.577

Gnomad OTH exome AF: 0.567

GnomAD4 exome AF: 0.565 AC: 826142 AN: 1461816 Hom.: 234767 Cov.: 92 AF XY: 0.563 AC XY: 409262 AN XY: 727200

African (AFR) AF: 0.447 AC: 14980 AN: 33480

American (AMR) AF: 0.542 AC: 24234 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 14550 AN: 26136

East Asian (EAS) AF: 0.510 AC: 20264 AN: 39700

South Asian (SAS) AF: 0.476 AC: 41044 AN: 86258

European-Finnish (FIN) AF: 0.595 AC: 31768 AN: 53358

Middle Eastern (MID) AF: 0.599 AC: 3454 AN: 5768

European-Non Finnish (NFE) AF: 0.577 AC: 642008 AN: 1111996

Other (OTH) AF: 0.560 AC: 33840 AN: 60396

GnomAD4 genome AF: 0.535 AC: 81278 AN: 152046 Hom.: 21985 Cov.: 33 AF XY: 0.534 AC XY: 39715 AN XY: 74316

African (AFR) AF: 0.451 AC: 18705 AN: 41484

American (AMR) AF: 0.549 AC: 8397 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 1967 AN: 3472

East Asian (EAS) AF: 0.495 AC: 2547 AN: 5148

South Asian (SAS) AF: 0.471 AC: 2269 AN: 4822

European-Finnish (FIN) AF: 0.584 AC: 6165 AN: 10552

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.582 AC: 39529 AN: 67964

Other (OTH) AF: 0.536 AC: 1133 AN: 2114

Alfa AF: 0.537 Hom.: 9125

Bravo AF: 0.528

Asia WGS AF: 0.465 AC: 1619 AN: 3478

EpiCase AF: 0.577

EpiControl AF: 0.571

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.82
DANN	Benign	0.53
PhyloP100		-0.90
Mutation Taster		=100/0	polymorphism (auto)

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: rs9441941; hg19: chr1-223178561; COSMIC: COSV52656581;