rs71469813

Variant names:

• chr11-686935-T-C
• rs71469813
• NM_021008.4:c.727A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BS1 BS2

The NM_001367390.1(DEAF1):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,614,250 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (18 hom.)
• Consequence: DEAF1 NM_001367390.1 start_lost
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.11
• Publications: 7 publications found

Genes affected

DEAF1 (HGNC:14677): (DEAF1 transcription factor) This gene encodes a zinc finger domain-containing protein that functions as a regulator of transcription. The encoded proteins binds to its own promoter as well as to that of several target genes. Activity of this protein is important in the regulation of embryonic development. Mutations in this gene have been found in individuals with autosomal dominant cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

DEAF1 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 24

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• intellectual disability-epilepsy-extrapyramidal syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• complex neurodevelopmental disorder

  Inheritance: SD Classification: STRONG Submitted by: Illumina
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 27 pathogenic variants. Next in-frame start position is after 46 codons. Genomic position: 684906. Lost 0.140 part of the original CDS.
• BP6: Variant 11-686935-T-C is Benign according to our data. Variant chr11-686935-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 434931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0027 (412/152366) while in subpopulation NFE AF = 0.00462 (314/68032). AF 95% confidence interval is 0.0042. There are 1 homozygotes in GnomAd4. There are 173 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 18 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367390.1. 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
	DEAF1	NM_021008.4	MANE Select	c.727A>G	p.Met243Val	missense	Exon 5 of 12	NP_066288.2
	DEAF1	NM_001367390.1		c.1A>G	p.Met1?	start_lost	Exon 5 of 12	NP_001354319.1	A0A804HIS1
	DEAF1	NM_001440885.1		c.1A>G	p.Met1?	start_lost	Exon 4 of 11	NP_001427814.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEAF1	ENST00000382409.4	TSL:1 MANE Select	c.727A>G	p.Met243Val	missense	Exon 5 of 12	ENSP00000371846.3	O75398-1
	DEAF1	ENST00000527170.5	TSL:1	n.88A>G		non_coding_transcript_exon	Exon 2 of 10	ENSP00000431563.1	H0YCH1
	DEAF1	ENST00000683307.1		c.1A>G	p.Met1?	start_lost	Exon 5 of 12	ENSP00000507198.1	A0A804HIS1

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 412 AN: 152248 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00461

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00277 AC: 697 AN: 251202 AF XY: 0.00285

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00480

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00507 AC: 7405 AN: 1461884 Hom.: 18 Cov.: 33 AF XY: 0.00487 AC XY: 3539 AN XY: 727238

African (AFR) AF: 0.00122 AC: 41 AN: 33480

American (AMR) AF: 0.00150 AC: 67 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00379 AC: 99 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86258

European-Finnish (FIN) AF: 0.000543 AC: 29 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00612 AC: 6811 AN: 1112008

Other (OTH) AF: 0.00548 AC: 331 AN: 60396

GnomAD4 genome AF: 0.00270 AC: 412 AN: 152366 Hom.: 1 Cov.: 33 AF XY: 0.00232 AC XY: 173 AN XY: 74518

African (AFR) AF: 0.00106 AC: 44 AN: 41590

American (AMR) AF: 0.00170 AC: 26 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00462 AC: 314 AN: 68032

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00408 Hom.: 4

Bravo AF: 0.00299

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00721 AC: 62

ExAC AF: 0.00264 AC: 320

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00562

EpiControl AF: 0.00498

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	DEAF1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.52	N
PhyloP100		2.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.10
Sift	Benign	0.10	T
Sift4G	Uncertain	0.034	D
Polyphen		0.14	B
Vest4		0.27
MVP		0.52
MPC		1.5
ClinPred		0.0051	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.095
gMVP		0.63
Mutation Taster		=96/4	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: rs71469813; hg19: chr11-686935; COSMIC: COSV100102087; COSMIC: COSV100102087;